Frontiers in Clinical Drug Research – Anti Allergy Agents [1 ed.] 9781681081595, 9781681081601

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Frontiers in Clinical Drug Research Anti Allergy Agents (Volume 2) Editor

Atta-ur-Rahman, FRS Kings College University of Cambridge Cambridge UK

Frontiers in Clinical Drug Research – Anti Allergy Agents

First published in 2016

Volume: 2 Editor: Prof. Atta-ur-Rahman ISSN (Online): 2214-6938 ISSN: Print: 2452-3194 ISBN (eBook): 978-1-68108-159-5 ISBN (Print): 978-1-68108-160-1 © 2016, Bentham eBooks imprint. Published by Bentham Science Publishers – Sharjah, UAE. All Rights Reserved.

© Bentham Science Publishers – Sharjah, UAE. All Rights Reserved.

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CONTENTS Preface Contributors

i iii

CHAPTERS 1.

Inflammatory Mediators and Neuromodulators: Targeting in Asthma and Chronic Obstructive Pulmonary Disease Soledad Gori, Julieta María Alcain, Gabriela Salamone and Mónica Vermeulen

2.

Allergic Asthma Pathogenesis and Antioxidant Therapy Li Zuo, Lei Ni and Chia-Chen Chuang

3.

Antioxidants as a Therapeutic Option in Inflammatory Liver Diseases with a Metabolic Origin María de Fátima Higuera-de la Tijera and Alfredo Israel Servín-Caamaño

4.

Medical Treatment of Allergic Rhinitis Tolgahan Catli, Deniz Hancı and Cemal Cingi

5.

Nothing to be Sneezed at: Th2 Cytokines as Novel Therapeutic Targets for the Production of Anti-Allergy Agents Nayyar Ahmed and Cenk Suphioglu

6.

7.

Peripheral and Central Inflammation Caused by Neurogenic and Immune Systems and Anti-Inflammatory Drugs Akio Hiura, Hiroshi Nakagawa, Eiichi Kumamoto, Tao Liu, Tsugumi Fujita, and Chang-Yu Jiang

3 45

80 106

122

149

Anti-Allergy Agents, from Past to Future Howayda M. Hassoba, Ranya M. Hassan and Mohamed A. Mandour

207

Index

244

The designed cover image is created by Bentham Science and Bentham Science holds the copyrights for the image.

i

PREFACE The second volume of Frontiers in Clinical Drug Research – Anti Allergy Agents comprises seven comprehensive chapters covering various aspects of clinical drugs used for treating the allergic conditions contributed by leading researchers in the field. In the first chapter, Vermeulen and colleagues focus mainly on the commonly occurring pulmonary tract ailments. They discuss the inflammatory mediators and neuromodulators that play a significant role in these diseases. They have provided a comprehensive overview of the novel therapeutic targets; histamine, acetylcholine and cysteinyl-leukotrienes, with emphasis on the advantages and shortcomings of the clinical trials carried out. In the second chapter, Zuo et al. discuss the various antioxidants available from supplements and diet that are potentially useful for the treatment and prevention of asthma. The pathogenesis of allergic asthma and its correlation with inflammation and ROS/OS are presented. In chapter 3, Higuera-de la Tijera and ServínCaamaño highlight the role of anti-oxidants in managing the inflammatory liver diseases with a metabolic origin, for minimizing the oxidative stress. Cingi and colleagues review the management therapies for allergic rhinitis in chapter 4. The different pharmacological therapies and recent advancements in the field of Allergic Rhinitis (AR) are presented including the treatment of pediatric AR patients. In chapter 5, Suphiglu and Ahmed present a comprehensive overview on Th2 cytokines as the new therapeutic target for the development of anti-allergic agents. They have highlighted the important targets, cytokines IL-4 and IL-13 and their receptors, that are key factors in the allergic cascade. Nakagawa et al., in chapter 6 present the role of algogenic substances (chemicals and natural products), their receptors, and anti-inflammatory drugs interrupting receptors, channels, and intracellular messengers, mainly in peripheral sensitization. They also discuss thermosensing TRP channels and IL-1β. TRP channels are closely correlated with itching and inflammation. In the final chapter of this eBook, Hassoba and colleagues present a comprehensive overview on allergic disorders and anti-allergy agents from almost all aspects in light of various contributions. I would like to thank all the contributors for their painstaking efforts in putting together an outstanding collections of reviews that comprehensively cover various aspects of this important field. I am also grateful to the excellent team of Bentham Science Publishers, especially Dr. Faryal Sami and Mr. Shehzad Naqvi led by Mr. Mahmood Alam, Director Bentham Science Publishers.

Atta-ur-Rahman, FRS Honorary Life Fellow Kings College University of Cambridge Cambridge UK

iii

CONTRIBUTORS Akio Hiura

Department of Oral Histology, School of Dentistry, Department of Pediatric Dentistry, Tokushima University Hospital, University of Tokushima, 3-18-15 Kuramato cho, Tokushima 770-8504, Japan

Alfredo Israel ServínCaamaño

Gastroenterology Department and Internal Medicine Department, Unit 108, “Hospital General de México, Dr. Eduardo Liceaga”, Mexico City, Mexico

Cemal Cingi

Department of Otorhinolaryngology, Faculty of Medicine, Osmangazi University, Eskisehir, Turkey

Cenk Suphioglu

NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, Victoria 3216, Australia

Chang-Yu Jiang

Department of Physiology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan

Chia-Chen Chuang

Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA

Deniz Hancı

Department of Otorhinolaryngology, Liv Hospital, Istanbul

Eiichi Kumamoto

Department of Physiology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan

Gabriela Salamone

Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

Hiroshi Nakagawa

Department of Pediatric Dentistry, Tokushima University Hospital, University of Tokushima, 3-18-15 Kuramato cho, Tokushima 7708504, Japan

Howayda M. Hassoba

Clinical Immunology Unit, Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Egypt

Julieta María Alcain

Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina

Lei Ni

Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA and Department of Pulmonary Medicine, Ruijin Hospital, School of

iv

Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China Li Zuo

Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA

María de Fátima Higuera-de la Tijera

Gastroenterology Department and Internal Medicine Department, Unit 108, “Hospital General de México, Dr. Eduardo Liceaga”, Mexico City, Mexico

Mohamed A. Mandour

Clinical Immunology Unit, Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Egypt

Mónica Vermeulen

Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

Nayyar Ahmed

NeuroAllergy Research Laboratory (NARL), School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Geelong, Victoria 3216, Australia

Ranya M. Hassan

Clinical Immunology Unit, Clinical Pathology Department, Faculty of Medicine, Suez Canal University, Egypt

Soledad Gori

Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina

Tao Liu

Center for Laboratory Medicine, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China and Department of Pediatrics, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China

Tolgahan Catli

Department of Otorhinolaryngology, Bozyaka Teaching and Research Hospital, Izmir, Turkey

Tsugumi Fujita

Department of Physiology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan

Frontiers in Clinical Drug Research: Anti-Allergy Agents, Vol. 2, 2016, 3-44

3

CHAPTER 1

Inflammatory Mediators and Neuromodulators: Targeting in Asthma and Chronic Obstructive Pulmonary Disease Soledad Gori1,2, Julieta María Alcain1, Gabriela Salamone1,2 and Mónica Vermeulen1,2,* 1

Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria, IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina and 2Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina Abstract: The most common diseases affecting respiratory tract are bronchial asthma and chronic obstructive pulmonary disease (COPD). Both pathologies involve the genesis of an inflammatory response that induces airway hyperresponsiveness (AHR) and obstruction. Differences between both may include the cellular component: eosinophilia in atopic asthma and neutrophilia in COPD and also the nature of AHR which is generally reversible in asthma whereas in COPD this phenomenon culminates with the complete reduction of airflow. Because it represents the major global cause of disability and death, countless efforts have been underway for decades to develop therapies to alleviate their symptoms. Despite the fact that asthma is the result of a Th2 response in which IgE antibody is the main effector mechanism, the use of antibodies against cytokines of this profile did not show effectiveness until now. This could be because asthma is a multifactorial disease, depends also on the differentiation of TCD8+ lymphocytes type Tc2/Tc17 during the chronicity of the process. In contrast to asthma, inhaled glucocorticoids in COPD have a limited effect in resolving inflammatory symptoms, which could explain the high dependence on noxious stimuli such as smoke that aggravates the obstructive disease. The drugs tested so far cover the two main aspects of these pathologies: inhibition of a) functionality or activation of inflammatory response or b) tissue remodeling. In the first place, systemic antagonist of H1 and H2 receptors were widely used for decades in asthma as antipruritic and central sedatives, however their anti-inflammatory effects were modest, despite their important local effects in allergic reactions affecting skin such as dermatitis, rhinitis and conjunctivitis where the integrity of the epithelial barrier is more important in its genesis. Also, montelukast, an antagonist of cysteinyl-leukotriene C4 appears to affect both the inflammatory response and lung structure being successfully used in pediatric asthma. On the other hand, therapies with β2-agonist or anticholinergic drugs, widely used in COPD, have been shown to improve airway inflammation thickening. *Corresponding author Mónica Vermeulen: Laboratorio de Células Presentadoras de Antígeno y Respuesta Inflamatoria. IMEX-CONICET, Academia Nacional de Medicina, Pacheco de Melo 3081, 1425. Buenos Aires, Argentina; Tel: +54 11 4805 9034/3664/5759 Ext 289/255; Fax: 54 11 4807-9071; E-mail: [email protected] Atta-ur-Rahman (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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This review aims to provide a comprehensive overview of the available literature on the novel therapeutic targets; histamine, acetylcholine and cysteinyl-leukotrienes, with emphasis on the benefits and disadvantages of these clinical trials.

Keywords: Acetylcholine, asthma, bronchodilators, COPD, histamine, inflammatory mediators, leukotrienes, muscarinic receptors, therapeutic strategies, 2-agonists. ASTHMA AND COPD EPIDEMIOLOGY Different studies published on asthma prevalence determined that the disease is characterized by a large geographical variability, even between rural and urban areas, and it is most common in children and the elderly. This variability is not relevant in COPD. The relationship between smoking and COPD is remarkable, having this habit a significant effect on its prevalence. However, it is unclear why only 15-20% of smokers develop the disease. Furthermore, several reports concluded that COPD prevalence is about 10% for those aged between 40 and 69 and 23% in men between 60 and 69 years, therefore a 12% of patients attend the first consultation around 65 years. Although COPD appears in adult life with a tendency to increase the prevalence with age, a small group of patients with antitrypsin deficiency can develop the disease at early ages, representing only 1% of all people affected by COPD. As mentioned, the opposite is observed in asthma, which is more common among children, the situation is reversed in adulthood, and returns to be more prevalent among males over 70 years, so it is not unusual to see patients whose first asthma manifestation appears in this age. Also, it is suspected that about 10% COPD patients concomitantly suffer asthma. As noted, the prevalence of both diseases is not negligible and they are one the main cause of consultation both in primary care and in pulmonology. Asthma is associated with airway hyperresponsiveness, as evidenced by its obstruction post-bronchodilator on spirometric test between another challenge tests. A main feature of many asthmatic patients is associated with remission of symptoms and relief after corticosteroids treatment; however, a small percentage of patients develop airway obstruction that does not remit after anti-inflammatory therapy. On the contrary, bronchodilator airway obstruction is the key symptom of COPD, usually accompanied by acute exacerbations and emphysema. Moreover, a main difference with asthmatic patients is that COPD is associated to significant side

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FCDR: Anti-Allergy Agents, Vol. 2 5

effects or comorbidity; such as cardiac failure, ischemia, osteoporosis, metabolic disorders and obesity [1]. Both diseases have many similarities but higher differences, corresponding to natural history, treatment response and mainly, anatomical, pathophysiologic and inflammatory response. ASTHMA PATHOLOGY For several years allergic asthma was defined as a typical Th2 adaptive pathology. The presence of allergen specific Th2 lymphocytes through their secretion of IL4, IL-5, IL-13 and IL-9 induce, in the lung, inflammatory features responsible for asthmatic symptoms: increased production of specific IgE by B cells, eosinophil and basophil recruitment and airway hyperreactivity (AHR). However, now it is clear that asthma as a heterogeneous pathology involves more than adaptive immunity. In this sense, the importance of dendritic cells (DCs), mast cells and epithelial airway cells in the activation of the adaptive response was extensively studied. This complex syndrome presents more than one phenotype including allergy and non-allergy forms that do not require an adaptive response. Recently, the importance of innate cells was demonstrated: NKT, and innate lymphocytes (ILCs) was demonstrated [1, 2]. Late Phase

Early Phase Allergen FCRI

Mast cell

IL-5

Eosinophil

FCRI Preformed mediators Histamine Lipid mediators LTs, Prostaglandins

Bronquial lumen Bronchoconstriction vasodilation Mucus production

Th2 cell CD8+ T cell

IL-4

Mast cell TNF-α,IL-4

chemokines LB

Activate Mast cell

LTs, PAF

Major basic protein (MBP) Cationic protein

Blood vessels Inflammatory cells recruitment

Tissue damage Bronchoconstrition

Fig. (1). Schematic representation of two main effector phases in allergy asthma.

IgE

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Mast cells, basophils and eosinophils exert a central role in the airways as inflammatory cells, however a growing consensus in favor of their action as antigen presenting cells, (APC) activating the development of immunity Th2 is increasingly accepted (Fig. 1). Both mast cells and basophils are characterized by the expression of the high affinity IgE receptor (FcεRI) and the amplification of the hypersensitivity reaction via the release of histamine and IL-4 [3, 4]. Later, the entry of eosinophils to the site of inflammation keeps the response at the expense of cysteinyl leukotrienes (CysLTs) and IL-5 [5] secretion. INNATE IMMUNITY Almost 80% of patients with asthma are sensitized to environmental allergens such as fungi, dust mite and pollens. In contrast, the rest of patients are not sensitized to environmental antigens such as pollution (cigarettes, diesel, aspirin), viral infection or obesity. During the last years innate cells NKT and ILCs [6] gained importance as the promoters of the inflammatory response in non-allergic patients (Fig. 2). Thus, human and mice NKT cells recognize lipid antigens through the non-classical presenting molecule CD1d [7]. Its signaling via this molecule induces the secretion of cytokines of different profiles: Th1 (FN-), Th2 (IL-4, IL-13) and Th17 (IL-17) with the ability to activate different leukocyte populations [8]. Their activation by lipid motifs present in fungi causes a severe inflammatory response [9]. The activation of the NKT cells causes the secretion of IL-33 by the alveolar and interstitial macrophages, which culminates with the amplification of the hypersensitivity reaction mediated by the activation of inflammatory granulocytes and Th2 lymphocytes [6]. Also, an important role to another innate lymphocyte with the ability to trigger Th2 profiles in the lung after their interaction with non environmental stimulus has been recently demonstrated. These ILCs non related to B or T lymphocytes, characterized by the production of IL-5, IL-13 and IL-9, were named type 2 (ILCs2). These cytokines enable them to induce mucus, eosinophilia and high serum levels of IgE, IgG1 and IgA that affect both intestinal and lung tissues. The first indications came from studies in airway alveolar macrophages infected with the influenza virus that induces the production of IL-33, conducive to the expansion of ILCs2 which, by releasing IL-13/IL-5 cytokines, results in AHR [10]. Further evidence strongly demonstrated that asthma patients with respiratory viral infections suffer rapid exacerbations leading to activation of innate lymphocytes independently of Th2 activation. ADAPTIVE RESPONSE As previously mentioned, classically asthma results from a Th2-dependent response, IgE mediated allergic disease. The uptake of exogenous antigens (Ags)

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by macropinocytosis in fluid phase or by receptor-mediated endocytosis [11, 12] mediated by DCs has a central role, as the generated peptides are efficiently presented to T cells by the molecules of the major histocompatibility complex (MHC) class II. On the contrary, the peptides originated in the cytosol are presented in a MHC class I context. However, exogenous Ags can be presented via this pathway, a process known as cross presentation, which enables DCs to present extracellular Ags associated with class I molecules, culminating in the activation of CD8+ responses. Antigen cross-presentation is not only relevant in anti-viral and tumor responses but it is also very important in the induction of chronic inflammatory pathologies [13]. Epithelial cell Mucus

Airway epithelium Allergens IL-25 TSLP IL-33 ILC2 CD4+ T cell

Lymph node Mediastinum

IL-9 IL-13

IgE

N K NKT T IL-33

Immature DC/ Alveolar macrophage

IL-4/IL-33 FCRI

HISTAMINA; CysLT PDE2,

CD8+ cell

B cell IL-5

Eosinophils CD4+ T cells

Fig. (2). Dendritic cells (DCs) process and present antigen determining a Th2 response. Other cells also are able to initiate a Th2 response after non allergy stimuli (ILC2, NKT; innate cells) or allergen-challenge (mast cells, basophils, eosinophils). PgE2: prostaglandin E2, FCεRI: high affinity receptor for IgE, HIS: histamine, CysLT: cysteinyl leukotrienes.

It was demonstrated in experimental models and in asthmatic patients that hyperinflammatory responses in the respiratory tract and lung not only are dependent on activation of CD4+ cells, but also the activation of CD8+ T lymphocytes is essential in the chronic phase (Fig. 2). These cells represent a

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particular subtype of CD8+ cells called Tc2 (Th2“like”), relative to the production of cytokines of Th2 profile [14, 15]. They produce IL-5, IL-4 and IL-13 and express the high affinity receptor of leukotriene B4 (LTB4) [16], and differ functionally from the Tc1 type or IFN- producer cytotoxic lymphocytes. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) COPD is an inflammatory airway disease and the number of people affected by it is increasing every year. This disease is characterized by chronic inflammation produced in the lung because of toxic particles and gases (pollution, smoke). It is primarily manifested by the stenosis of the smaller airways, hypersecretion of mucus and parenchyma destruction or emphysema, which concludes in the loss of the elasticity of lung tissues [1,17].

Fig. (3). Noxious stimuli impact on the epithelial barrier and alveolar macrophages and activate inflammatory mechanisms that progressively lead to respiratory failure.

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It affects 5% of the population and has a high mortality and morbidity. Macrophages play a central role in the inflammation of COPD. The irritants and the smoking habit induce inflammation on the peripheral airways and the lung parenchyma, which in turn activate macrophages to produce and to secrete several mediators such as TNF-α, IL-6, IL-8, monocyte-chemotactic peptide (MCP)-1, LTB4, reactive oxygen species and proteolytic enzymes (MMP-9, MMP-12), whose action contributes to the induction of emphysema (Fig. 3). Also, neutrophils which are recruited into the respiratory tract via the IL-8 and LTB4 release play a significant role [18], due to overstimulation of mucous glands and the goblet cells through the release of proteinases such as cathepsine G, neutrophil elastase and proteinase-3 [19, 20]. Dendritic cells [21] and epithelial cells [22] have a remarkable role in COPD, mainly because the DCs constitute the nexus between the noxious particles, thanks to their privileged position near the surface and the immune response activating macrophages, neutrophils, and adaptive immunity (T and B lymphocytes). It should be mentioned that COPD patients’ lung biopsies showed the presence of CD4+ and CD8+ lymphocytes. Interestingly, CD8+ cells through the secretion of perforins, granzyme-B and TNF- [23] promote the apoptosis of alveolar epithelial cells associated with emphysema. On the other hand, epithelial cells in the airway and alveoli are the major source of inflammatory mediators and proteases. Smoke induces the release of IL-8, IL1β, TGF-β, TNF-α and granulocyte-macrophage colony stimulating factor (GMCSF), which cause activation of fibroblasts and fibrosis [24, 25]. A final paragraph to the oxidative stress [26] consequence of the production of active free radicals by activated inflammatory and epithelial cells in the respiratory tract, which promote the deep damage of lipids, proteins and DNA; characteristic feature of the pathophysiology of disease. UNIQUE CHARACTERISTICS OF BRONCHIAL EPITHELIUM Epithelium has the ability to secrete several mediators that deeply impact on the integrity of mucosal tissue. Among them the cytokine Thymic Stromal Lymphopoietin (TSLP) gained importance a few years ago, through modulation of the crosstalk between the epithelium-DCs and/or mast cells orientating the response into a Th2 profile which includes eosinophil recruitment and IgE production [27]. This secretion by epithelial cells could be potentiated by IL-4 and

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IL-5, mechanism that amplifies the inflammatory response. Moreover, basal cells can secrete their nuclear storage of IL-33 after epithelial damage which, through its interaction with ILCs2 cells, maintains the polarization of the response to a Th2 profile. Likewise, IL-8 release by airway epithelium after injury or infection, the major neutrophil chemo-attractant has a central role in COPD but also in certain genotypes of asthma [28, 29], allowing the mucosal recruitment of neutrophils which enhance cytolysis and inflammatory response. On the other hand, the lipoxins (LX), acting as natural “braking signals”, regulate the inflammation and promote their resolution [30]. Many isoforms of LX produced with intervention of the lipooxigenase (LO) were reported. Under normal conditions the epithelium produces a particular type, the 15-LO [31] which increases in asthmatic patients, at the expense of inflammatory leukocytes, inducing airway injury [32, 33]. Finally, epithelium expresses a wide variety of receptors. Among them are the glucocorticoid receptors, the epidermal growth factor (EGF), and many neuromodulators such as acetylcholine (Ach) and norepinephrine (NE) [34]. This fact makes of the epithelium a central target for developing new anti-inflammatory therapies. MANAGEMENT OF ASTHMA AND COPD It is known that corticosteroids are the main therapeutic choice when treating the chronic inflammation of asthmatic patients. By contrast, although COPD is a disease of clear inflammatory etiology, corticosteroids have not proven effective. In this line, changes in neutrophil recruitment, proteases and inflammatory mediators were observed after their administration. An interesting fact, that may explain their differential action in both pathologies, is that corticosteroids have an opposite effect on the survival of inflammatory cells: while they increase the survival of neutrophils, they decrease that of eosinophils [35]. In recent years, the bronchial epithelium has assumed a central role [34] as the target to improve the usual therapy for managing chronic inflammation. This fact could explain how in COPD the nature of inflammation and harmful compromise of the integrity of the epithelium inhibits the responsiveness to corticosteroids. Although this therapy is more effective in asthma, in 20% of asthmatic patients

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the steroids are not suitable, and it is increasingly recognized that in these patients there is a great injury of the bronchial epithelium and increased recruitment of neutrophils and T CD8+ lymphocytes which resemble COPD disease: this is called severe steroid resistant asthma [36]. In the last years, the treatment of both diseases was dominated by using fixed-dose inhalers formulated with long or short-acting β2-agonist (LABA and SABA; respectively) and corticosteroids (ICS). Combined therapies between SABA or LABA with short-acting muscarinic receptor antagonists (SAMA), as well as LABA are also widely used as bronchodilators for the treatment of patients with COPD and more severe asthma. Indeed, several inhaled medicines containing various combinations of three of these pharmacological drugs, so-called triple inhalers [37-40], are underway. Although the administration of corticosteroids is the standard anti-inflammatory therapy for respiratory diseases, it has significant systemic and local side-effects. Despite the existence of several anti-inflammatory drugs [2-3], most have few benefits in the treatment of patients with severe asthma [41], or COPD [42]. The failure could be because these drugs are directed against a single inflammatory mediator [43-46]; suggesting that the complexity of the inflammatory response in both asthma and COPD requires drugs with actions on more than one biological target. Thus, several drugs have been developed with bifunctional anti-inflammatory activity, including antagonists for the inflammatory receptors such as plateletactivating factor and histamine, in combination with rupatadine, a blocker of mast cell secretion [37, 47]. Another example is the combination of the thromboxane receptor and cysteinyl-leukotriene antagonists in the same molecule [48-49]. However, these types of drugs have shown only limited efficacy until now, at least in the treatment of allergic airway diseases. Finally, in mice the use of a bifunctional drug which targeted both murine cytokines IL-4 and IL-13 [4, 50], was able to reduce the serum IgE levels IL-4-dependent, IL-13-mediated airway hyperresponsiveness, lung inflammation, and mucin gene expression in mice. Currently, this therapy is being tested in humans affected with COPD and fibrosis associated with asthma with promising results [51]. Finally, it should be noted that the chosen therapy will depend largely on the phase of the disease in both pathologies (See Tables 1 and 2). In this review, we discuss the latest advances in the treatments of asthma and COPD with emphasis on the blockade of inflammatory mediators such as histamine and cysteinyl leukotrienes as well as the main neurotransmitters; acetylcholine (Ach) and norepinephrine (NE).

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Table 1. Characteristic of asthma symptomatology. Rescue and maintenance therapy. Sex

Side effects

Female 16-64 years

CSS alterations Hallucinations Anxiety Sleep disturbances Extreme agression, irritability Sleep and behavioral disturbances In few cases CSS alterations

Male 9-48 years

Combined therapy ICS or β2-AR+ICS

Albutamol or β2-AR+LAMA

Remission of symptoms >24h< 2 months

>24 h 80

1. SABA

< 70

1. SABA 2. LABA

II: Dyspnea moderate and cough (eventually) III: grave

Dyspnea and cough (usually)

IV: severe Respiratory failure

30-50

< 30

Therapy none

1. SABA 2. LAMA or combined with LABA 4. ICS 1. SABA 2. LAMA or combined with LABA 4. ICS 5.Oxigen administration

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GENERAL CHARACTERISTICS OF LEUKOTRIENES Leukotrienes (LTs) are lipid mediators synthesized from the arachidonic acid present in cellular membranes. Inflammatory leukocytes, including mast cells, eosinophils, basophils, neutrophils and macrophages, produce them after their activation with several stimuli such as allergen and microorganisms. The enzyme 5-lipoxygenase (5-LO) produces the intermediate LTA4, which in the presence of LTA4 hydrolase originated the LTB4; only produced by neutrophils of COPD patients and neutrophilic asthmatics. LTC4, on the other hand, results from the action of LTC4 synthase, and it is quickly converted into its metabolites LTD4 and LTE4. This family of leukotrienes (C4, D4 and E4) was designated cysteinyl leukotrienes (CysLTs), they were the first ones identified in leukocytes and they are conjugated to the amino acid cysteine. Mast cells and eosinophils in asthma patients secrete predominantly CysLTs. Together with histamine are characteristic pro-inflammatory mediators of allergic and inflammatory reactions. They are potent spasmogens and inducers of mucus secretion [52, 53]. Their pharmacological effects are mediated through two membrane receptor types called: CysLTs receptor type 1 (CysLTR1) and type 2 (CysLTR2), which are G protein-coupled [54]. Remarkably, these receptors were described primarily in mucosal tissues associated to the airways and gut [53, 55]. The binding affinity to CysLTR1 is LTD4>LTC4>LTE4 and to CysLTR2 is LTC4=LTD4>LTE4. Meanwhile, the interaction of CysLTs via the CysLTR1 induced bronchoconstriction, edema and mucus via the CysLTR2 results in airway inflammation and fibrosis. Surprisingly, the low affinity of LTE4 to both receptors suggests the existence of a specific receptor for this mediator [56]. Moreover, the LTB1R and the LTB2R are the receptors that recognize LTB4. INVOLVEMENT OF LTs IN INFLAMMATORY REACTIONS Asthma is a chronic inflammatory disease characterized by the destruction of the respiratory tract, including small pulmonary vessels which culminating with difficulty to breath. Airway hyperresponsiveness to inhaled stimulus is a central feature of this pathology. Direct stimuli such as methacholine act on the smooth muscle cells of the airways trigger bronchoconstriction. Also, indirect stimuli such as exercise or inhalation challenges (cold air, mannitol, hypertonic saline among others) induce bronchospasm via the release of mediators by inflammatory cells. Cysteinyl leukotrienes, prostaglandins, histamine and acetylcholine are some of the mediators implicated in the pathophysiology of bronchoconstriction caused by indirect challenges in asthma [4].

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It is believed, however, that the CysLTs play a main role in the pathogenesis of acute and chronic asthma, because they are the most potent bronchoconstrictors described in humans to date. The normal tone of human airways is the result of the balance between mediators that induce contraction like leukotrienes (CysLTs and LTB4) and histamine, and others than induce muscle relaxation [57, 58] such as prostaglandin E2. This means that during the chronic phase of asthma, the increased contractility is mainly due to an increase in CysLTs [59, 60]. The remarkable contractile activity of LTC4 and LTD4 in isolated human bronchi was described about three decades ago and was confirmed in vivo in healthy humans [61, 62]. The experimental data confirmed that CysLTs are one the most important inflammatory mediators in asthma because their high capacity to increase microvascular permeability, which leads to the production of pulmonary edema, increased mucus secretion associated with the reduction of the mucosal clearance, due to decrease cilia and hyperplasia of smooth muscle cell, leading in term to disruption of the integrity of the airway activity [63-65]. It is known that during the early phase of allergy the major producers of CysLTs are the mast cells and subsequently during the late, eosinophils. In this sense, an association between increasing levels of CysLTs and eosinophilia was observed in bronchial lavage and urine of asthmatic patients [66]. Given the key role exerted by eosinophils in the process of chronic inflammation associated with asthma, it was shown that the CysLTs increase the survival of these cells in response to paracrine signals from mast cells and lymphocytes. In addition, eosinophils also express CysLTR1 mediating several autocrine actions. The CysLTs promote maturation and migration of leukocytes from the bone marrow into the circulatory system. These mediators are chemoattractants for eosinophils, and increase the cell adherence and the transendothelial migration through the vessel wall of the respiratory tract [67]. CURRENT TRIALS THAT USE ANTAGONISTS OF CysLTs Currently, imaging techniques such as the computed tomography (CT) and more precisely the high-resolution CT (HRCT) enable detailed examination of airways, which is highly relevant because their structure and functionality are compromised in chronic asthma and COPD [68]. CysLTs are important mediators in airway remodeling. Since 2010, several trials intended to test the efficacy to use antagonists of CysLTs in human asthma and COPD to ameliorate the airway physiology. The general consensus focusing exclusively on pediatric asthma recommended that leukotrienes antagonist receptors (LTRAs) may be chosen as a first-line alternative treatment for persistent asthma. Much evidence supports the use of oral montelukast, the antagonist of CysLTR1, as an initial controller

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therapy for mild asthma in children, since it reduces bronchoconstriction and airway inflammation [69, 70]. Further, antagonists of leukotrienes are advised such a therapy for those in which the ICS does not prevent symptoms [71-73]. Notably, recent studies aim to evaluate whether montelukast could reverse airway remodeling in asthma patients of a wide range of ages, by a non-invasive approach-HRCT. In this line, it was recently demonstrated [74] in patients with severe-to-moderate asthma, that the addition of montelukast daily to LABA/ICS combined therapy improves lung function measured as air trapping but not airway wall thickening, in these patients. Although this clinical trial lasted 24 weeks and taking into account the results obtained in animal models [75, 76], long-term studies will be required to analyze the effect of montelukast on airway remodeling. In this regard, it is encouraging that Kelly et al. [77] demonstrated in mild-asthmatic patients that montelukast attenuates fibrosis induced after exposure to allergen. Usually, leukotriene receptor antagonist (LTRAs) is currently prescribed for all asthmatics. It is only effective in certain types of asthma, such as exercise-induced bronchoconstriction, aspirin-intolerant asthma, infection-induced asthma and smoking. This is a consequence of increased CysLTs levels and resistance to corticosteroids and β2-agonists too. In fact, the use of LTRAs (such as montelukast, pranlukast) diminishes the inflammatory symptoms and improves pulmonary function [78-80]. During Hypertonic Saline challenge, the secretion of CysLTs is increased as was demonstrated by the acute diminution of bronchoconstriction in the presence of a CysLTR1 antagonist. The trend toward inhibition of bronchial responsiveness is greater with three weeks of CysLTR1 antagonism treatment [81]. It was extensively demonstrated that plasma levels of LTC4 are increased in subjects suffering from COPD as well as LTE4 during its exacerbations [82, 83], which would indicate that CysLTs/LTs might play a role in the persistent bronchoconstriction produced in COPD. In a clinical study of Nannini et al. (7) it was demonstrated that the use of a single dose of the antagonist of LTD4, zafirlukast (ZK; 40mg), has a quick bronchodilator effect after its administration. Likewise, in this trial a functional correlation between the ZK and the β2adrenergic agonist, salbutamol, was observed in terms of the forced expiratory volume (FEV1), indicative of the absolute respiratory capacity of a patient. The FEV1 is expressed as a percentage and represents the air exhaled by the lung during 1 second in a forced way and after having inspired a maximum volume of air. When this percentage drops to 75 (the normal value in healthy people), it is

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indicative of obstructive lung disease such as COPD. Hui et al. [85] previously found a FEV1 of approximately 45% as measure of the maximum bronchodilation in patients with stable COPD and moderate smokers. A correlation between ZK and salbutamol was not found. In another study [84], the value of FEV1 was reported around 35%. Differences between studies could depend on the history of patients. Thus, the correlation between cigarette smoke and CysLTs was demonstrated, which was associated to the pathophysiology of COPD as one of the causes of persistent brochoconstriction and mucus hypersecretion [83, 86]. Also, an increase in urine LTE4 levels in asthmatic patients, which was exacerbated in smokers, was demonstrated [87]. On the contrary, in COPD subjects this mediator was not affected compared to asthmatics and healthy volunteers. It should be noted that in this assay LTC4 levels are not reported, making it difficult to compare across studies, because LTC4 is generally reported in these pathologies. Both in asthma and COPD, sequential metabolism of LTC4 provides extracellular LTD4 and LTE4, which strongly maintains bronchoconstriction [85, 88, 89]. The inflammatory response in COPD in susceptible smokers leads to an accelerated decline in FEV1 that is inherent to resistance to inhaled corticosteroids [90]. It should be emphasized that even those who had quit smoking, showed an increased number of inflammatory cells in the airways [91]. Higher numbers of CD8+ T cells are present in the lungs of patients with COPD, but many other cells responsible for the pathology could be the source of LTs [92-93]. The cysteinyl leukotriene receptor 1 has been extensively studied and it was responsible for the majority of the pro-inflammatory mechanisms of LTs. However, there are still discrepancies since it was found that the use of ZK inhibited LTs induced bronchoconstriction in healthy subjects [94]. Because ZK only inhibits the D4 mediator, perhaps the mediator responsible for airways contraction is another CysLTs. Therefore, which one is the suitable antagonist to improve symptomatology must be deeply analyzed. In the last 5 years, the study of LTs antagonist use was intensified, not only as bronchodilators but as anti-inflammatory drugs. Celik et al. [95] showed a significant increase in the FEV1, in the arterial oxygen pressure and also an important increase in the quality of life after 2 months of montelukast treatment. In sputum samples of the montelukast treated group, a notable decrease in neutrophilic activity was shown. In a recent study, the montelukast treatment of patients with stable COPD for over 12 months caused a decreased in serum levels of LTB4, IL-8, and TNF-α, as well as the inhibition of dyspnea and expectoration

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and decrease in the number and duration of hospitalizations [96]. On the contrary, results of Woodruff et al. [97] reported that the use of zileuton, a 5-lypoxigenase inhibitor, does not decrease the hospitalization length. A plausible explanation of these differences could be that most clinical studies were conducted in patients with stable COPD, while the trial of Woodruff was made during acute exacerbations. It can also be mentioned that while the dose of zileuton was 600 mg 4 times per day, the Celik trial was done with a single daily dose of 10 mg of montelukast, probably producing a systemic saturation of zileuton, and leaving non responder patients. It should be mentioned that daily doses of these mediators in chronic asthma and COPD usually range around 1200 mg; on the contrary, in this trial the doses used are twice as much which might explain the toxic effects observed. For the management of moderate-to-severe asthma the indication for children include LTRAs and a 5-lipoxygenase inhibitor. Two LTRAs are available, montelukast (for patients >1 year of age) and ZK (for patients ≥7 years of age). The 5-lipoxygenase pathway inhibitor zileuton is available for patients ≥12 years of age; liver function monitoring is essential. LTRAs are an alternative, but not preferred, therapy for the treatment of mild persistent asthma. LTRAs can also be used as adjunctive therapy with ICS, but for young ≥12 years of age and adults they are not the preferred adjunctive therapy compared to the addition of LABA. Zileuton can be used as an alternative but not preferred adjunctive therapy in adults. One of the most important benefits of LTRAs use is the inhibition of recruitment/production of LTB4 from innate immune cells [98, 99]. The LTB4 interaction through a specific cell surface receptor, BLT1, that induces accumulation of neutrophils and macrophages at sites of inflammation was widely demonstrated [16]. Extensive evidence suggests that accumulation of CD8+ T cells is in part dependent of the LTB4/BLT1 pathway. Also, CD8+ effector lymphocytes express the BLT1 receptor, so the LTB4 released into the lung mucosa allows their income from the node area, maintaining and enhancing the inflammatory response. UNWANTED EFFECTS OF MONTELUKAST The use of montelukast can develop a syndrome named Churg-Strauss in asthmatic patients when they are deprived of corticosteroids. This syndrome is characterized by eosinophilia, vasculitis, rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy [100]. Montelukast is classified into risk

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category B in pregnancy [101], taking to account it crosses the placental barrier. However, motelukast has shown no evidence of teratogenic effects in laboratory animals and there are not controlled clinical studies in pregnancy; its administration is not recommended unless the benefits to the mother outweigh the possible risks to the fetus. In a recent review of Calapai et al. [102], there is a detailed study of cases reported so far in which montelukast is the choice therapy and its toxic effects. Notably, the main side effects of montelukast are associated to temporal alterations of the central nervous system (Table 3). Table 3. Main non-desirable effects after anti-LTs treatment.

HISTAMINE BACKGROUND Histamine is a bioactive amine that plays a central role in a variety of processes such as neurotransmission, gastrointestinal and circulatory functions as well as inflammation responsible for allergic reactions [103, 104]. Histamine is produced via the decarboxylation of the amino acid histidine mediated by the enzyme Lhistidine decarboxylase. Mast cells and basophils store histamine in association with proteoglycans. Certain leukocyte populations such as neutrophils, macrophages, DCs and T lymphocytes do not store histamine but are capable to produce and release high amounts of histamine after their activation [105, 106]. For years, there has been great interest to explore the immunoregulatory mechanisms induced by histamine, however, there are conflicting data regarding its pro- or anti-inflammatory effects, which depend largely on the degree of expression of its 4 receptors (H1, H2, H3 and H4) in each cell, associated with its

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rapid degradation and the high turnover of membrane receptors along the immune response. It has been widely documented that the histamine modulation of allergy involves primarily the H1 receptor. The use of H1R antagonists proved successful in controlling clinical symptoms such as pruritus and vasoconstriction in diseases like rhinitis or conjunctivitis, but it showed no effectiveness in asthma [107, 108]. This could be explained considering that asthma has a multifactorial pathogenesis, in this sense, the development of a Th2 response is essential for Ag sensitization and early inflammatory response, while the chronicity of the process is dependent on recruitment of CD8+ Tc2 lymphocytes [109]. On the other hand, H4R is expressed in the lung mainly on leukocytes and in low proportions in the bronchial epithelium [110]. Relative to their role in allergy, from a model of mice deficient in this receptor, in which inflammation of the airways was induced with ovalbumin, it was found that H4R induces chemotaxis of mast cells, eosinophils and DCs and is also involved in cytokine production by DCs and T lymphocytes [111-113]. INVOLVEMENT OF HISTAMINE IN ASTHMA Histamine exerts a central role in the development of allergic reaction through its action on smooth muscle, airway tone and mucus secretion. It is released from mast cells in the airway or by circulating basophils in response to immunological (anti-IgE or cytokines) or non immunological (hyper-osmolarity, substance P, calcium ionophore, opioids inter alia) [114] stimuli. Histamine is metabolized by histamine N-methyltransferase (HMT) to N-methylhistamine, and subsequently in the presence of monoamine oxidase becomes the N-methylimidazole acetic acid, the major urinary metabolite. Only 3% is excreted as the unmodified form. HMT has a great expression in airway epithelial cells modulating the local histamine metabolism. In fact, the SKF 91488 a blocker of HMT enhances bronchoconstriction mediated by histamine in vitro and in vivo [115]. Despite histamine is considered a good marker of allergy, its measurement in circulation is complicated, because the urinary dosage of its stable metabolites does not reflect their release from mast cells in the airways [116], together with its spontaneous release by basophils, which may contribute to the elevate concentrations observed in asthmatic patients. A good strategy would be collected the sample near to the site of histamine release. While intravenous sampling arm, after mast cells degranulation, triggered by substance P shows an increase in plasma histamine concentrations [117], this sampling is not feasible in the

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airways. By contrast, assessing histamine levels in bronchoalveolar lavage fully reflects what happens at the level of the airways. Histamine concentrations are elevated in this fluid of asthma patients, both at rest and after allergen challenge [118, 119], it was reported extensively. The source of histamine is presumed to be mucosal mast cells, and the contribution of infiltrating basophils is unclear. ANTIHISTAMINES Histamine mediates most of its effects on airway function via H1 receptors, for years assumed as a great candidate in airway disease. While nonsedating H1 receptor antagonists, such as terfenadine, loratadine, and astemizole, may be given in large doses and show clinical effectiveness in allergic rhinitis, they are far from effective for asthma patients, as demonstrated in clinical trials [120]. In general, antihistamines, even at high doses, have not significant clinical effects [121]. Terfenadine causes approximately 50% inhibition of the immediate response to allergens, but has no effect on the late response. Antihistamines cause a small degree of bronchodilation in asthmatic patients, indicating a certain degree of histamine “tone”, presumably resulting from the basal release of the amine from activated mast cells, as discussed above. Chronic administration of terfenadine has a small clinical effect among patients with mild allergic asthma [122] but is far less effective than other anti-asthma therapies; therefore, these drugs cannot be recommended for the routine management of asthma. Other antihistamines, such as cetirizine and azelastine, have been shown to have beneficial effects in asthma [123, 124]; which do not seem to be related to their H1 antagonist effects [125]. H2 antagonists, such as cimetidine and ranitidine, may be contraindicated in asthma on theoretical grounds, if H2 receptors are important in counteracting the bronchoconstricting effect of histamine. In clinical practice, however, there is no evidence that H2 antagonists have any deleterious effect on asthma. H3 receptor agonists may have some theoretical benefit in asthma, because they may modulate cholinergic bronchoconstriction and inhibit neurogenic inflammation. Although (R)-a-methylhistamine relaxes rodent peripheral airways in vitro [126], it has no effect, when given by inhalation, on airway caliber or metabisulfite-induced bronchoconstriction in asthmatic patients, indicating that a useful clinical effect is unlikely [127]. Despite the fact that histamine is a central mediator in allergic reactions causing both early symptoms such as itching and sneezing as well as late phase symptoms; nasal congestion and rhinorrhea, H1 antagonists that proved effective in countering the effects associated with the epithelial-endothelium airway tissues (vasodilation, vascular permeability, edema, smooth muscle contraction, sensory

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nerve endings), are only relevant in intermittent or acute allergic reactions such as rhinitis or conjunctivitis, but not as a palliative in asthma or chronic diseases. FIRST STEPS IN THE USE OF ANTIHISTAMINES The blocking agents of H1Rs activation became the first-line therapy for both intermittent and persistent allergic rhinitis [128]. They have been termed H1 antihistamines as opposed to H1 antagonists that can only block the action of agonists. The first H1 antihistamine was discovered in 1937 [129]. This compound, despite being effective, showed several adverse effects, causing sedation and other side effects as blurred vision, constipation, tachycardia, dry mouth, urinary retention and memory deficits. Its central side effects are due to its ability to cross the brain blood barrier and block the H1Rs in the central nervous system [130, 131]. Most side effects have been associated with functional blockade of muscarinic receptors [128]. Because of these facts, it was not suitable for the treatment of allergy patients. Later, the generation of second-generation compounds, provided the first successful nonsedating antihistamines. However, despite the improved receptor selectivity, potentially fatal adverse cardiac effects, such as specific polymorphic ventricular tachyarrhythmia, related to blockade of specific cardiac K+ channels by these second generation antihistamines, generated their withdrawal from the market [132]. At the end, a series of compounds with no cardiac or sedative effects came out (Loratadine, Cetirizine, Fexofenadine and Ebastine). It should be noted that antihistamines are the most commonly prescribed medications in children, particularly to treat acute allergic reactions, allergic rhinitis and urticaria to mitigate the effects induced by histamine [133]; on the other hand, they are not the first choice in chronic processes. A separate paragraph, for the development of dual drugs, characterize by the presence of an antagonist of histamine receptors and the chemokine receptor of eotaxin; the CCR3. The eotaxin produced by fibroblasts, alveolar macrophages and eosinophils after their recognition by CCR3 induces the recruitment and activation of eosinophils, basophils and Th2 lymphocytes. The CCR3-H1 antagonists were developed to inhibit degranulation of mast cells and eosinophil recruitment. A clinical trial reported a beneficial effect with the compound AZ3778, which displays activity for human CCR3 receptor and functional H1 antagonism. These compounds act as loratadine, reducing the symptoms of rhinitis [134]. Contrary to loratadine, the AZD-3778 improved nasal peak inspiratory flow and the cationic protein of eosinophil as a measure of allergic inflammation. However, in this area still remain more clinical trials to test its effectiveness and whether it could replace corticosteroids.

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NEW INSIGHTS IN H4 RECEPTOR LIGANDS The H4 receptor has a 37 to 43% homology with the H3R, their transcripts were only observed on hematopoietic cells; although their expression was initially demonstrated in human eosinophils [135], it was later shown in neutrophils, dendritic cells, T helper cells, mast cells and basophils [136, 137]. Their interaction with most of the immune and non immune cells culminates with the inhibition of cAMP and increased cytosolic Ca2+. This fact makes it inevitable to study histamine in detail since its expression usually is affected during the normal immune response as well as in pathological processes such as atherosclerosis, rheumatoid arthritis, and allergic rhinitis [103,138,139]. In a recent work, in a mouse model of skin inflammation it was demonstrated that not only the H1R but also the H4R has an essential role in the induction of Th2 polarization [140]. Moreover, Czemer et al. [141] reported that histamine induces chemotaxis and phagocytic activity by bone marrow-derived macrophages. Notably, both functions are dependent on H4R, since the use of its antagonists, thioperamide and JNJ7777120 reduced it [142], while the H1 antagonist has no effect. One of the most promising therapeutic applications of H4 antagonists is atopic dermatitis. High expression levels of H4R mediated histamine-induced proliferation have been already described in atopic dermatitis, and JNJ7777120 demonstrated an inhibitory effect [143]. It has been also shown that JNJ7777120 effectively inhibits histamine and TNF-α-induced mRNA expression of IL-8 in the HaCaT keratinocyte cell line. This indicates that IL-8 mRNA expression might be modulated via H4R in keratinocytes [144]. Finally, in a guinea pig asthma model, the pre-treatment with JNJ7777120 reduced allergic asthmatic symptoms and airway inflammation [145], an effect associated with lipocortin-1 (inhibitor protein of lipid mediators) up-regulation. Thioperamide [143] partially minimized the effects of JNJ7777120 in an asthma model, while some effects as the titers of allergen-specific IgE, inflammatory infiltration in lung tissues, were only observed with JNJ7777120 [5], which can be attributed to its agonist effect. We have demonstrated that through their action via H1R/H4R the histamine increases the presentation of soluble ovalbumin on class I molecules [146] by DCs, inducing the recruitment of type 2 TCD8+ lymphocytes in the lung [147]. Considering the importance of this leukocyte in the chronicity of inflammatory response in asthma, future research will be needed. In this sense, the use of dual antagonists of LTs/anti-histamine was extensively analyzed in allergic rhinitis with encouraging results. Actually, many clinical trials evaluated the effect of montelukast together with antihistamines in asthmatic patients.

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The ability of histamine to stimulate cross-presentation in DCs via H3R and/or H4R may represent a novel mechanism through which mast cells, the major cellular source of histamine, modulate the course of the adaptive immune response. Moreover, it is now becoming clear that allergen-specific CD8+ T cells are important contributors to the development of allergic responses in the lung. They appear to be required for the development of both, airway hyperresponsiveness and eosinophilic airway inflammation [148, 149]. INTRODUCTORY ASPECTS OF AUTONOMIC NERVOUS SYSTEM OF THE AIRWAYS The knowledge of the airways innervation is critical to the design of bronchodilators because alterations of autonomic nervous system contribute to the development of asthma and COPD. In brief, the autonomic nervous system has a central role in the regulation of smooth muscle tone in the airways, which is regulated by the vagus nerve [150]. The input of excitation and inhibition is mediated by the cholinergic and noradrenergic system through their neurotransmitters: acetylcholine and norepinephrine (NE) released into synapses holding the contraction/relaxation at the level of postganglionic neurons and the parasympathetic ganglia [151]. It was also reported, [152] the existence of the nonadrenergic noncholinergic (NANC) or nitrergic relaxation of the airways [152, 153]. In fact, autonomic neural control of airways smooth muscle tone cannot be fully explained by the functions of the cholinergic and adrenergic nervous system alone. There is substantial evidence of contractile and relaxant NANC smooth muscle responses in mammalian airways [151]. So, bronchospasm could be evoked by increases in cholinergic nerve activity or the recall of nitrergic neural activity. Conversely, increased nitrergic nerve activity or decreased cholinergic tone could elicit bronchodilation [154]. In humans and in many animal species, adrenergic nerves are sparse or absent in the airways and without apparent influence over the airway smooth muscle tone [155]. Consequently, nitrergic parasympathetic nerves represent the only functional relaxant innervation of airway smooth muscle mediate NANC neurotransmitters such as nitric oxide (NO) and vasoactive intestinal peptide (VIP) and related peptides [154]. Thus, there is no direct sympathetic innervation of airway smooth muscle, although the airway vasculature does receive sympathetic innervation [156]. There is evidence, however, for a sympathetic input of parasympathetic ganglia and β2-adrenoceptors (ARs) on airway smooth muscle.

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SYMPATHETIC NERVOUS SYSTEM IN THE AIRWAYS The preganglionar sympathetic nerve fibers form cholinergic synapses with postganglionic sympathetic adrenergic neurons that extend to the lung to release NE on effector targets such as the submucosal mucus gland and blood vessels. Despite the lack of direct sympathetic innervation of airway smooth muscle, ARs are present throughout the lung [157]. Furthermore, sympathetic fibers innervate the parasympathetic ganglia allowing communication between the two systems. NE and hormonal catecholamines, such as epinephrine, act via α and β-ARs [151]. Despite the limited role of sympathetic adrenergic nerves regulating airway function, these nerves may play a prominent role in regulating the airways in asthma under some conditions. Elevated sympathetic nerve activity has also been associated with COPD [158]. β-ARs are present in high concentration in lung tissue and are localized in several cell types. Three types of β-ARs: β1, β2 and β3; members of the seventransmembrane family of G protein-coupled receptors (GPCRs) were described. Approximately 70% of pulmonary β-ARs are β2 and are localized in the: airway smooth muscle, epithelium, vascular smooth muscle, and submucosal glands [157], whereas β1 receptors are confined to glands and alveoli. High levels of β2 are found in the alveolar region with a greater distribution in small more than large airways. β2 receptors are also expressed on many inflammatory leukocytes such as mast cells, neutrophils, macrophages, lymphocytes, eosinophils and also in epithelial, endothelial and type I and II alveolar cells. β2-ARs stimulation produces airway relaxation, however prolonged stimuli lead to unresponsiveness or receptor desensitization. Whether β2-ARs stimulation can evoke the activation of cholinergic neurotransmission is controversial. So, Aizawa et al. have suggested that the stimulation of prejunctional β2-ARs on parasympathetic ganglia inhibits cholinergic neurotransmission [159], on the contrary, Haas et al. identified a direct excitatory activity on β2-ARs in airway parasympathetic nerves [151]. MECHANISM OF ACTION OF Β2-AR AGONISTS While β2-AR agonists modulate the relaxation of the airway smooth muscle they became effective bronchodilators. The use of these agonists inhibits the signaling triggered by contractile stimuli on airway smooth muscle [160]. Agonists interacting with β2-ARs coupled to Gs (stimulatory G protein), activate adenyl cyclase (AC) and increase AMPc. Then, AMPc activates final effector molecules

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as PKA (cAMP-dependent protein kinase A) and Epac, a Rap1 guanine nucleotide exchange factor [160]. So, the modulation of contraction/relaxation of the airway smooth muscle tone depends on the second messenger involved. Other agents such as prostaglandin E2 and phosphodiesterase inhibitors also increase intracellular levels of cAMP in the airway smooth muscle, can also antagonize airway smooth muscle contraction, and also inhibit other function of the airway smooth muscle including proliferation and migration. Therefore, β2ARs agonists and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, there are limitations to the use of β2AR agonists due to tachyphylaxis related to β2-ARs desensitization [161]. PHARMACOKINETICS OF Β2-AR AGONISTS The β2-AR agonists may be administered in two different ways: intravenously or through an inhaler. Inhalers are one of the most important ways to treat people with severe acute asthma, allowing the localized delivery of low doses of a drug, combining rapid clinical response with less systemic side effects [162]. Metereddose inhaler (MDIs) devices are best used to provide treatment to patients with COPD and asthma, comprising approximately 70% of the bronchodilator prescriptions [163]. When β2-AR agonists are administered by inhalation, the therapeutic effect depends on local tissue concentrations that may not be directly related to plasma drug concentrations. Although very little of the inhaled dose of β2-AR agonists reaches the airways, this small amount produces effective bronchodilation [162]. Systemic drug concentrations are the result of drug absorption through the pulmonary vascular bed and also through the gastrointestinal tract, the latter being the most important effect: After inhalation 20% of the dose reaches the lungs while most is lost through the oropharynx and therefore may reach the systemic circulation from the gastrointestinal tract. β2-AR agonists are eliminated through the systemic circulation [162, 164]. CLINICAL USE OF Β2-AR AGONISTS The first types of non-selective β-AR agonists described were effective bronchodilators but structurally similar to catecholamines and did not discriminate between β1 and β2-ARs, with cardiac side effects. The formulation of selective β2AR agonists did not begin until the discovery of albuterol or salbutamol, in the late 60s. It is important to note that the β-AR agonists differ from selective β2-AR

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agonists by their structure which determines their resistance to metabolism by the catechol-0-methyltransferase (COMT). As a result, these non-catecholamine β2AR agonists have a longer half-life than non-selective β-AR agonists [165]. This varied between different β2-AR agonists and determined its actual classification: 1.

SABA; short-acting drugs as Albuterol or Salbutamol, Fenoterol and Terbutaline, with 4-6 h of effect.

2.

LABA; long-acting drugs approximately 12 h of effect.

3.

Ultra-LABA; once-a-day ultra-long-acting β2-AR agonists as Indacaterol, Olodaterol, Vilanterol, with 24 h of effect. These were approved in the last two years, while others such as Abediterol, Carmoterol are still in clinical phase [166, 167].

as

Formoterol

and

Salmeterol,

Independently of the classification, the β2-AR agonists act by mimicking some of the effects of epinephrine: (1) inhibition on airway smooth muscle and the release of mediators from mast cells; (2) stimulation of the heart, leading to increase of heart rate, contraction, and conduction; (3) metabolic actions (e.g., glycogenolysis in liver and skeletal muscle, resulting in an increase of glucose); (4) endocrine actions (increasing insulin and glucagon release); (5) prejunctional action on parasympathetic ganglia, increasing or decreasing acetylcholine releases. In addition, they may also have anti-inflammatory properties of granulocytes, epithelial cells and fibroblasts [168, 169]. Furthermore, this class of drugs also protects against the actions of bronchoconstrictor stimuli. SABA are currently used as rescue therapy for obstructive lung disease, because their short half-life limits their use as maintenance therapy. They can be divided into two groups according to the duration of action after inhalation of conventional doses: 1) the catecholamines and rimiterol isoprenaline, which have very short action of 1-2 h; and 2) conventionally described as short-acting as fenoterol, albuterol or salbutamol and terbutaline, which are assets of 3-6 h, although fenoterol action can be a bit longer [165]. By contrast, LABA and Ultra-LABA are used as maintenance therapy because they provide 12-24 h of bronchodilation (salmeterol/formoterol and indacaterol, respectively). Although, they are not able to influence the accelerated decline in lung function characteristic of COPD, at least in terms of clinically significant changes, offer greater comfort for patients with COPD. They induce significant

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improvements in FEV1, reduce dynamic hyperinflation and improve exercise tolerance by decreasing dyspnea [151]. They also reduce the frequency of exacerbations of COPD and offer a potential survival advantage. By contrast, in asthma LABA effectiveness can only be guaranteed if used in combination with an inhaled corticosteroid (ICS) in the appropriate dose, preferably in a single inhaler device [170]. In fact, while providing effective relief of symptoms and improvement in lung function, LABA can mask the underlying inflammation that may develop, or the need to increase the dose of ICS, leading to more exacerbations and uncontrolled asthma mortality as documented by the Salmeterol Multicenter Asthma Research Trial (SMART) [171]. SIDE EFFECTS OF Β2-AR AGONISTS A number of clinical studies have found that regular use of β2-AR agonists had adverse effects on the control of asthma and COPD. β2-AR agonists mainly exert their clinical effects in the lung, but multiple tissues and cell types also have functional and physiologically relevant β2-ARs [172]. First, it should be noted that the β2-AR agonists should be supplied at the lowest possible dose and frequency; to decrease the probability of an adverse effect [169, 173]. However, the large variability between patients and between studies of FEV1 with bronchodilators makes the determination of optimum dosages difficult. In addition, patients with severe COPD as those with acute exacerbations require higher doses to achieve optimal bronchodilation [174]. Many unwanted effects are produced by the β2-agonists, including heart rate and palpitations, since the atria and ventricles are β2-AR, selective β2-agonists can result in the direct simulation of cardiac tissue. Also, the stimulation of β2-ARs can lead to vasodilation and reflex tachycardia with increased inotropic and chronotropic effects [173]. Notably, inhaled β-agonists increase blood sugars [172], therefore must be used with caution in diabetic patients to prevent ketoacidosis. Also stimulate insulin secretion in a glucose dependent manner, as seen with several other enhancers of insulin secretion [172]. The side effect over the blood sugar regulation is of minor importance, except in diabetic patients, whose disease is likely to be aggravated by the use of systemic corticosteroids in situations of severe asthma [173]. Another risk with β2-agonist treatment is the Hypokalemia [162] resulting from stimulation in skeletal muscle of the Na+, K+-ATPase-driven pump coupled to βARs [173]. This increases the ability to push Na+ out of the cell and facilitates intracellular accumulation of K+, thereby lowering plasma levels. This effect

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together with the use of corticosteroids and diuretics aggravate the condition. Therefore, the use of β2-agonists is linked to an increased incidence of tachyarrhythmia [151]. On the other hand, Futamura et al. [169] found that β2-AR agonists use increased TSLP production by airway smooth muscle cells and lung fibroblasts as well as bronchial epithelial cells. This is an important cytokine that is necessary and sufficient for the initiation of allergic inflammation. In fact, high expression of TSLP was also described in the airways of patients with COPD. This would explain the harmful effects of continuous β2-agonist therapy. CURRENT COMBINATION THERAPY The indication of the use of combination therapy (LABA plus ICS) in asthmatic patients to avoid exacerbations emerged from several randomized clinical trials. In this regard, evidence resulting of two randomized controlled trials (RCTs) shows that monotherapy using the LABA salmeterol increases the risk of mortality, in patients with unstable asthma private of the ICS therapy [177]. In fact, the FDA and the Global Initiative for Asthma (GINA) contraindicate the use of LABA monotherapy for asthma in patients of all ages without other control drugs as ICS and recommends the use of SABA such as medications of choice for quick relief of bronchospasm during acute exacerbations of asthma. Moreover, data in asthmatic children are not convincing increasing doses of ICS over LABA combination is preferred [175, 176]. In contrast, Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends the use of LABA in all patients with COPD, although it does not prefer β2-agonists to LAMA. Relative to the route of administration of these medicaments and based on efficacy and side effects, inhaled bronchodilators are preferred over oral agents. The β2-agonists can be combined with LAMA when the symptoms are not controlled by monotherapy, and they can be combined with ICSs in patients with less than 50% FEV / or frequent exacerbations uncontrolled by long-acting agents. The novel triple combination therapies such as LABA + LAMA (tiotropium bromide) + ICS improves lung function, COPD symptoms and health status, and reduce the risk of hospitalizations compared with tiotropium bromide alone in patients with moderate and severe COPD [166]. The current strategies suggested by the Guidelines GINA, GOLD and FDA are the following [177]: a.

LABA+ICSAsthma

b.

Ultra-LABA+ICSAsthma

Inflammatory Mediators and Neuromodulators

c.

LABA+LAMACOPD

d.

Ultra-LABA+LAMACOPD

e.

LAMA+ICS COPD

f.

Another combination possible:

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 LABA-LAMA+Phosphodiesterase InhibitorCOPD  ICS+Theophyline (alkaloid to prevent wheezing) Asthma/COPD  LABA+LAMA (tiotropium bromide)+ICSCOPD  LABA+LAMA+PDE4 inhibitorsCOPD PARASYMPATHETIC NERVOUS SYSTEM IN THE AIRWAYS Airway tone is mainly controlled by the vagus nerve, and the parasympathetic nerves carried in the vagus nerve are tonically active, producing a stable, readily reversible baseline tone of the airway smooth muscle [150]. Preganglionic parasympathetic nerve fibers project to the airways via the vagus nerve and form cholinergic synapses with postganglionic neurons via airway parasympathetic ganglia. Airway parasympathetic ganglia are associated mainly with the larger airways, but the subsequent postganglionic fibers innervate structures throughout the airway tree [40]. CHOLINERGIC SYSTEM Acetylcholine (Ach) is an endogenous neurotransmitter of both the peripheral and central nervous systems where it is synthesized, stored, and released from cholinergic nerve terminals [178]. Ach is the primary parasympathetic neurotransmitter in the airways; it is synthesized from acetyl coenzyme A (acetylcoA) and cytoplasmic choline of autonomic presynaptic nerve terminals after catalysis by the enzyme choline acetyltransferase (ChAT). This is transported packaged into synaptic vesicles that contain between 1,000 and 50,000 molecules. When an action potential reaches the presynaptic neuron, an influx of calcium causes exocytosis of the vesicles and the acetylcholine attaches to the various receptors on the postsynaptic membrane [179].

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Two types of Ach receptors belonging to the family of the seven-transmembrane family of GPCRs are been recognized: nicotinic and muscarinic. The signaling pathways activate by these receptors includes the adenyl cyclase, phospholipase C, and potassium channels [179]. The parasympathetic stimulation through muscarinic receptors is the responsible of bronchoconstriction and mucus secretion in the airways. Moreover, there are also evidence that Ach regulates inflammatory cell chemotaxis and activation, and participates in the signaling events responsible for chronic airway remodeling associated with asthma and COPD. For this reason, the blockade of muscarinic receptors acquires significant importance for the management of both pathologies [180]. Five subtypes of muscarinic receptors have been described (M1–M5), differentially expressed on the airway smooth muscle, submucosal glands, inflammatory cell and nerves. The M1 receptors are widely distributed throughout the parasympathetic ganglia and exocrine glands; they are responsible for cholinergic transmission. The prejunctional muscarinic M2 autoreceptors are found in the smooth muscle and the myocardium, and these provide negative presynaptic feedback to reduce further release of Ach [181]. The M3 subtypes in the airway smooth muscle mediate bronchoconstriction and mucus secretion [182-184]. When they are coupled to G protein, M1, M3, and M5 have a stimulatory effect on the target tissue, whereas the M2 and M4 subtypes have inhibitory effects [184, 185]. The distribution of muscarinic receptor subtypes throughout the bronchial tree is mainly restricted to muscarinic M1, M2 and M3 receptors [186]. ANTICHOLINERGIC THERAPY Inhaled anticholinergics have been used for centuries as treatments for respiratory diseases. They are widely used for the treatment of COPD, and less frequent in asthma. The anticholinergic agents act as bronchodilators, and their rational use in asthma is based on the assumption that activation of the parasympathetic (cholinergic) nerve pathway is an important mechanism for producing airway obstruction [187, 188]. In humans, airway caliber is controlled by different ways. The parasympathetic system is one of many mechanisms, via the modulation of the bronchomotor tone. Taking into account the distribution of muscarinic receptors, anticholinergics such as atropine are competitive inhibitors of acetylcholine and may result in bronchodilation by reducing the tone of airway smooth muscle [189]. Anticholinergic agents appear to induce primarily the bronchodilation of the large airways, whereas β2-agonists relax both large and small airway constriction equally [190, 191].

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As previously mentioned, muscarinic antagonists (MA) used mainly in COPD as bronchodilators are classified as short-acting MA (SAMA; being ipratropium and oxitropium the most representative) and long-acting MA (LAMA; tiotropium), taking into account their half-life period [192]. SHORT-ACTING MUSCARINIC ANTAGONIST (SAMA) Atropine, a natural alkaloid, was the first anticholinergic bronchodilator agent identified from the Datura stramonium plant; but due to its great absorption into systemic circulation even at low doses, it lost clinical relevance consequence of its many side effects [179, 180]. This determined the commercial development of the β2-agonists ephedrine and epinephrine in the 1920s. Another derivative of atropine; the atropine methonitrate [194, 195] demonstrated better like-albuterol bronchodilator effect in asthma patients [196]. However, in the 1970s, the Ipratropium bromide, a quaternary ammonium synthetic analogue of atropine, was developed and this compound gave few systemic side effects and anticholinergic drugs recovered interest [193]. Unlike atropine, it has low lipid solubility and does not cross the blood-brain barrier. Ipratropium bromide is poorly absorbed by the oral and nasal mucosa, and the swallowed drug is poorly absorbed from the gastrointestinal tract [197]. When administered via inhalation at therapeutic doses of 20 t 40µg, ipratropium bromide is somewhat less effective than SABA in patients with asthma [198] and less effective than LABA in patients with COPD [199]. Considering that Ipratropium was a relevant therapy with minor systemic side effects, it allowed for the development of new agents, such as the Oxitropium and Tiotropium bromides [179, 182, 200]. The peak of bronchodilation by Oxitropium bromide may take 60–90 min, and its effective duration is 5–8 h. Oxitropium’s bronchodilator effect is similar to ipratropium bromide, but oxitropium is longlasting [201-203]. The usual dose is 200 g, 2–3 times daily. It is considered to have twice the strength of ipratropium per dose. Despite being widely used for many years (alone or in combination with SABA) both for maintenance treatment of stable disease and exacerbation of airway obstruction [179, 204, 205], its high doses also cause tachycardia. The non-selective antimuscarinic drugs; atropine, ipratropium and oxitropium that successfully abrogate bronchoconstriction and airway hyperreactivity in humans; however, a serious problem of these drugs is that they bind M2 and M3 muscarinic receptors with equal affinity [206, 207]. The blockade of the M2

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receptor subtype allows further release of presynaptic Ach and may antagonize the bronchodilator effect of blocking the M3 receptor. LONG-ACTING MUSCARINIC AGONISTS (LAMA). A feature of these drugs is their durability compared to SABA. The long-lasting tiotropium bromide, which is an atropine congener and more potent brochodilator, has an approximate duration of 24 h, which makes it suitable for once-daily dosing to improve airway obstruction in COPD and asthma. The compound is structurally related to ipratropium bromide, constituting the second-generation anticholinergic agent introduced early in the last decade. The binding of tiotropium to muscarinic receptors have different times of dissociation being the shortest corresponding to complex tiotropium–M2 muscarinic receptor (3.6 hours) compared with M1 (14.6 hours) and M3 (34.7 hours versus 0.3 h for ipratropium) [182], conferring a more selective and pharmacology activity to M1 and M3 receptors [208-210]. After the first dose, the mean time to onset its effect is 30 min, and the mean time to peak effect is about 3 h; the maximum effect is obtained after 1 week [211-214]. The recommended dose is 18 g once daily and the fraction that reaches the lung is highly bioavailable; and it gives protection against inhaled methacholine challenge [210, 211]. It can be considered a drug of patient adherence [215, 216]. Plasma concentrations of tiotropium rapidly decline after dosing; therefore, the long duration of action of tiotropium bromide appears to be due to its slow dissociation from the M3 receptors in the lung [217]. Functionally, it improves lung function, dyspnea and health-related quality of life and reduces COPD exacerbations together with related hospitalizations [218]. The most common side effect of inhaled anticholinergics is dry mouth. This may be particularly pronounced in the elderly COPD patients, although this side effect does decrease over time, allowing the patient to maintain therapy without the need for withdrawal [219]. Tiotropium was not associated with statistically significant differences in cardiovascular mortality, cancer mortality, or mortality from other causes. A randomized controlled trial analyzed outcomes in 50 patients with COPD who received tiotropium plus pulmonary rehabilitation program or tiotropium alone show that the pulmonary rehabilitation program did not provide any additional significant benefit to patients who were already receiving tiotropium bromide [220].

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The growing evidence of the importance of tiotropium bromide in the maintenance treatment of COPD has stimulated further research to identify new long-acting mAChR antagonists that could be as successful as tiotropium bromide [221]. Several novel inhaled LAMAs are currently being developed, including glycopyrronium bromide, aclidinium bromide, umeclidinium bromide [151]. CONCLUSIONS AND PERSPECTIVES A paragraph apart deserves the allergen immunotherapy as the only curative method of allergy diseases by contrast to rescue and maintenance therapies described in this review for some mediators and neurotransmitters. Despite, the efficacy of sublingual immunotherapy for the treatment of rhinitis and asthma has been long established, however deleterious effects persist yet [222]. Among unwanted effects are the costs of these treatments, as prolonged time of therapy and find exactly the allergen that produces long-term tolerance. It should also be noted that in asthmatic patients with epithelial damage the allergen immunotherapy are not effective. This lead to try to generate new strategies of immunotherapy that improve the hypoallergenic therapy by recombinant derivatives of allergen which decrease IgE reactivity however, until the moment this was not effective because the induced response it is less than pure preparations. In fact, the new vaccine formulations used chimeras and fusion proteins as a way to bypass IgE responses, whereas induction of IgG responses are favored as mean to activate T regulatory responses [223, 224]. Based on the points developed throughout this review, we can generalize that during mild and moderate asthma the use of LT antagonists, typically montelukast, is highly beneficial and first line therapy primarily in pediatric cases, although today it is recommended for asthmatic subjects of all ages. Also, the management of COPD involves LABA and LAMA, among these last compounds mainly Tiotropium. Another is the result during the chronic phase of these pathologies. As clearly mentioned the fact of the higher heterogeneity of these diseases in regard to the mechanisms involved determining the current development of many strategies, such as phosphodiesterase inhibitors, matrix metalloproteinases, anti-cytokine antibodies, nanoparticles therapy, among others. In this context, recently a main importance has acquired the type 4 cyclic nucleotide phosphodiesterase (PDE4) it belongs to the family of cAMP specificphosphodiesterases. They have a catalytic domain and because their expression in several leukocytes determined that increasing levels of intracellular Ca2++, PDE4 inhibitors exert anti-inflammatory and bronchodilator effects improve the symptoms of chronic respiratory diseases [225]. For many years the clinical trials

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allowed with their approval (roflumilast) to treat COPD associated to chronic bronchitis and recurring exacerbations. Unfortunately, this therapy has potent side effects mainly at the gastrointestinal tract. Currently, many studies aimed to improve the clinical efficacy have shown that the formulation of a new generation of inhibitors with inhaled delivery might decrease side effects. Moreover, the most promissory strategy in this field is the dual combination of the PDE4-ICS or PDE4-PDE3. In the latter case phosphodiesterases act improving and prolonging the effects of LABA/ICS combined therapy [226, 227]. Concerning the mediators and neurotransmitters discussed in this review include therapies currently being developed that allow inhibition of GPCR receptors involved in these signaling mediators [228]. Finally, there are multiple protocols that attempt to determine the role of histaminergic H4 receptor in chronic asthma, which will lead to develop a combined therapy of antagonists of LTs/histamine or H1/H4. However, further studies are needed to prove its effectiveness as well as the exact role of each of these mediators. CONFLICT OF INTEREST The author confirms that author has no conflict of interest to declare for this publication. ACKNOWLEDGEMENTS The authors wish to thank the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), and Agencia Nacional de Promoción Científica y Tecnológica, Argentina for their support. REFERENCES [1] [2] [3] [4] [5] [6]

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[194] Altounyan RE. Variation of Drug Action on Airway Obstruction in Man. Thorax 1964; 19: 406-15. [195] Allen CJ, Campbell AH. Comparison of inhaled atropine sulphate and atropine methonitrate. Thorax 1980; 35(12): 932-5. [196] Pierce RJ, Allen CJ, Campbell AH. A comparative study of atropine methonitrate, salbutamol, and their combination in airways obstruction. Thorax 1979; 34(1): 45-50. [197] Simons FE. Anticholinergic drugs and the airways: "Time future contained in time past". J Allergy Clin Immunol 1987; 80(3 Pt 1): 239-42. [198] Cazzola M, Centanni S, Donner CF. Anticholinergic agents. Pulm Pharmacol Ther 1998; 11(5-6): 381-92. [199] Matera MG, Cazzola M, Vinciguerra A, Di Perna F, Calderaro F, Caputi M, et al. A comparison of the bronchodilating effects of salmeterol, salbutamol and ipratropium bromide in patients with chronic obstructive pulmonary disease. Pulm Pharmacol 1995; 8(6): 267-71. [200] Rau D, Brown AH, Brubaker CL, Attene G, Balmas V, Saba E, et al. Population genetic structure of Pyrenophora teres Drechs. the causal agent of net blotch in Sardinian landraces of barley (Hordeum vulgare L.). Theor Appl Genet 2003; 106(5): 947-59. [201] Minette A, Marcq M. Oxitropium bromide (Ba 253), an advance in the field of anticholinergic bronchodilating treatments. Preliminary results. Rev Inst Hyg Mines (Hasselt) 1979; 34(3): 115-23. [202] Flohr E, Bischoff KO. Oxitropium bromide, a new anticholinergic drug, in a dose-response and placebo comparison in obstructive airway diseases. Respiration 1979; 38(2): 98-104. [203] Frith PA, Jenner B, Dangerfield R, Atkinson J, Drennan C. Oxitropium bromide. Dose-response and time-response study of a new anticholinergic bronchodilator drug. Chest 1986; 89(2): 249-53. [204] Frith PA, Jenner B, Atkinson J. Effects of inhaled oxitropium and fenoterol, alone and in combination, in chronic airflow obstruction. Respiration 1986; 50(Suppl 2): 294-7. [205] Nakano Y, Enomoto N, Kawamoto A, Hirai R, Chida K. Efficacy of adding multiple doses of oxitropium bromide to salbutamol delivered by means of a metered-dose inhaler with a spacer device in adults with acute severe asthma. J Allergy Clin Immunol 2000; 106(3): 472-8. [206] Barnes PJ. Muscarinic receptor subtypes: implications for lung disease. Thorax 1989; 44(3): 161-7. [207] Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129(5): 856-70. [208] Lee AM, Jacoby DB, Fryer AD. Selective muscarinic receptor antagonists for airway diseases. Curr Opin Pharmacol 2001; 1(3): 223-9. [209] Barnes PJ. Tiotropium bromide. Expert Opin Investig Drugs 2001; 10(4): 733-40. [210] Haddad EB, Mak JC, Hislop A, Haworth SG, Barnes PJ. Characterization of muscarinic receptor subtypes in pig airways: radioligand binding and northern blotting studies. Am J Physiol 1994; 266(6 Pt 1): L642. [211] Maesen FP, Smeets JJ, Sledsens TJ, Wald FD, Cornelissen PJ. Tiotropium bromide, a new longacting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur Respir J 1995; 8(9): 1506-13. [212] Witek TJ, Jr. Anticholinergic bronchodilators. Respir Care Clin N Am 1999 Dec; 5(4): 521-36. [213] Littner MR, Ilowite JS, Tashkin DP, Friedman M, Serby CW, Menjoge SS, et al. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161(4 Pt 1): 1136-42. [214] Gross NJ. Tiotropium bromide. Chest 2004; 126(6): 1946-53. [215] Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002; 19(2): 217-24. [216] Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002; 19(2): 209-16. [217] Disse B, Speck GA, Rominger KL, Witek TJ, Jr., Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64(6-7): 457-64. [218] Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;(2): CD002876. [219] Tashkin DP, Cooper CB. The role of long-acting bronchodilators in the management of stable COPD. Chest 2004 Jan; 125(1): 249-59.

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[220] Lindsay M, Lee A, Chan K, Poon P, Han LK, Wong WC, et al. Does pulmonary rehabilitation give additional benefit over tiotropium therapy in primary care management of chronic obstructive pulmonary disease? Randomized controlled clinical trial in Hong Kong Chinese. J Clin Pharm Ther 2005; 30(6): 567-73. [221] Cazzola M, Matera MG. Emerging inhaled bronchodilators: an update. Eur Respir J 2009; 34(3): 75769. [222] Akdis CA, Akdis M. Advances in allergen immunotherapy: Aiming for complete tolerance to allergens. Sci Transl Med. 2015; 7(280): 280ps6. [223] Linhart B, Focke-Tejkl M, Weber M, Narayanan M, Neubauer A,Mayrhofer H, et al. Molecular Evolution of Hypoallergenic Hybrid Proteins for Vaccination against Grass Pollen Allergy. J Immunol 2015; 194(8): 4008-18. [224] Focke-Tejkl M, Weber M, Niespodziana K, Neubauer A, Huber H, Henning R, et al. Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy. J Allergy Clin Immunol 2015; 135(5): 1207-1217.e11. [225] Rogliani P, Calzetta L, Cazzola M. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Matera MG(1), Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs 2014; 74(17): 1983-92. [226] Moretto N, Caruso P, Bosco R, Marchini G, Pastore F, Armani E, et al. CHF6001 I: a novel highly potent and selective phosphodiesterase 4 inhibitor with robust anti-inflammatory activity and suitable for topical pulmonary administration. J Pharmacol Exp Ther 2015; 352(3): 559-67. [227] BinMahfouz H, Borthakur B, Yan D, George T, Giembycz MA, NewtonR. Superiority of combined phosphodiesterase PDE3/PDE4 inhibition over PDE4inhibition alone on glucocorticoid- and longacting β2-adrenoceptoragonist-induced gene expression in human airway epithelial cells. Mol Pharmacol 2015; 87(1): 64-76 [228] Baker KE, Bonvini SJ, Donovan Ch et al. Novel drugs targets for asthma and COPD: lessons learned for in vitro and in vivo models Pulm Pharmacol and Therap 2014; 29(2): 181-98.

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CHAPTER 2

Allergic Asthma Pathogenesis and Antioxidant Therapy Li Zuo1,*, Lei Ni1,2 and Chia-Chen Chuang1 1

Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA and 2 Department of Pulmonary Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China Abstract: Allergic asthma is a worldwide chronic inflammatory disease characterized by cycles of airway obstruction due to recurrent episodes of respiratory smooth muscle contraction and bronchoconstriction. Public awareness of asthma has increased over the past few decades due to higher prevalence, especially among younger generations. Many research efforts are dedicated to the understanding of this complex disorder and the role of genetic and environmental factors. Emerging evidence from animal studies and clinical trials has identified oxidative stress (OS) as an important factor contributing to asthma pathogenesis. In addition, observational epidemiologic studies suggest a possible correlation between impaired intake of antioxidants and increased prevalence of allergic asthma. The imbalance between antioxidants and oxidants in the respiratory airway due to overproduction of reactive oxygen species (ROS) or overwhelmed antioxidant system indicates a strong association between ROS and asthma. Although physiological levels of ROS are essential for the modulation of cell signaling pathway, excessive ROS production can lead to worsened physiological conditions, including increased airway hyperresponsiveness, epithelial shedding, vascular permeability, mucus secretion, as well as other inflammatory responses through the upregulation of proinflammatory mediators. In particular, the exposure to sources such as allergens, air pollution, and tobacco smoke, not only triggers airway inflammation, but also provides exogenous ROS. Simultaneously, overreacted immune responses exacerbate ROS formation, which furthers the inflammation. Redox therapeutics has become a potential approach in alleviating OS and restoring oxidant-antioxidant balance. However, redox therapeutics is limited by ineffective measurement of lung redox status due to the lack of standard biomarkers of OS and antioxidant capacity. Moreover, the responses to antioxidants are largely dependent on the stage of the disease, genetic susceptibility, and external sources of OS. These aspects also pose a great challenge to the redox therapeutics. The antioxidants, either antioxidant enzymes or non-enzymatic antioxidants, are frequently used in the treatment for multiple diseases, including *Corresponding author Li Zuo: Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus OH, USA; Tel: (614)292-5740; Fax: (614)292-0210; E-mail: [email protected] Atta-ur-Rahman (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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neurodegenerative, cardiovascular, skin, and liver diseases. Particularly, the intake of antioxidant supplements, such as vitamin C, and dietary changes are proposed to decrease asthma prevalence and enhance asthma control. However, limited data has displayed their beneficial effects on asthma subjects clinically. The exact mechanism by which ROS influence the lung tissue remains unclear. Future studies may be focused on the molecular mechanisms of redox processes as well as the development of treatments in allergic asthma. In this chapter, we will discuss the specific antioxidants from supplement and diet that are potential agents for the treatment and prevention of asthma. The pathogenesis of allergic asthma and its correlation with inflammation and ROS/OS will be presented. The development of potential biomarkers of OS and effective therapeutic redox intervention will be discussed in this chapter.

Keywords: Airway hyperresponsiveness, allergen, allergic asthma, antioxidant, FENO, inflammation, inhaled corticosteroids, oxidative stress, reactive oxygen species, vitamin. INTRODUCTION Asthma is a worldwide health issue affecting almost all age groups [1]. It is estimated that each year nearly 300 million people are diagnosed with asthma and approximately 250,000 deaths occur due to asthma [2]. Notably, the emerging urbanization is considered a contributing factor that leads to the estimation of 400 million asthmatic cases worldwide by the year of 2025 [2]. In developed countries, asthma-related expenditure may range from $300 to $1,300 (USD) per patient annually [2]. Despite substantial improvement on asthma management and prevention over the past few decades, asthma remains a large burden in the healthcare system [1]. In particular, asthma prevalence is increasing in children (Age < 18) [3]. In the United States alone, statistics have reported that pediatric asthma causes 14 million missed school days each year [4]. Asthma is generally recognized as a heterogeneous, chronic airway disease characterized by airway hyperresponsiveness (AHR) that persists even when the symptoms are absent or lung function is normal [5]. The commonly observed clinical symptoms of asthma include a history of episodic shortness of breath, wheeze, chest tightness, cough, as well as variable expiratory airflow limitation. These symptoms vary over time and in intensity. Some patients may experience episodic cough as the sole symptom, which tends to exacerbate particularly at night or in the morning. Exposure to factors such as allergens, ambient pollution, exercise, weather, viral respiratory infections (e.g., cold), and certain medications are known to trigger asthma [6].

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Allergic asthma and non-allergic asthma are two major phenotypes in the clinical classification [7, 8]. Currently, factors predisposing the development of these phenotypes are not fully elucidated [9]. However, it is reported that age at onset (general cut-off point of age 12) can help distinguish allergic asthma from other phenotypes [8]. As the most frequently observed asthma phenotype, allergic asthma often commences in childhood. It is highly associated with a family history of other allergic diseases such as eczema, allergic rhinitis, and food and drug allergy [10]. Prior to the treatment, patients with allergic asthma have shown a higher-than-normal sputum eosinophil count, indicating an eosinophilic inflammation in the airway. These patients frequently have a good response to treatment with inhaled corticosteroids (ICS) [11]. In contrast, non-allergic asthma clinically presents itself as a late-onset disease. Although similar AHR is evident in both allergic and non-allergic asthma, the sputum eosinophil count in nonallergic asthma remains normal. Moreover, patients with non-allergic asthma respond less favorably or even resist ICS therapy [6]. Unlike chronic obstructive pulmonary disease (COPD), which shares some similar characteristics with asthma and progresses in an irreversible trend, the symptoms of asthma are truly reversible [12]. Most of the treatments are effective in relieving asthmatic symptoms in a short period of time. Some symptoms can even be reduced spontaneously. The severity of asthma varies from time to time, yet acute symptoms, which usually occur within in a few minutes, can be lifethreatening. Severe asthmatics suffer from profuse sweating, shallow breathing, accessory muscle contraction and reduced airflow leading to a condition devoid of wheezing that is also known as “silent chest”. Such severe asthma exacerbations induce acute respiratory arrest and can be lethal if not treated immediately [6]. Physical examination is capable of identifying several abnormalities that characterize asthma, such as expiratory wheezing and lung hyperinflation. However, a careful examination on the patterns of respiratory symptoms is necessary to accurately diagnose asthma, since many symptoms tend to overlap and may not be entirely attributed to asthma [13]. Asthma is an umbrella term describing grouped clinical and pathophysiological features. Currently, the specific classification of asthma phenotypes is not fully established due to overlapped and complex molecular alterations. In general, asthma is widely regarded as an allergic, eosinophilic and Th2-mediated disease [8]. As a critical symptom of asthma, airway inflammation is largely manifested by the environmental exposures to allergens or pollutants, which provides exogenous oxidants and stimulates production of endogenous reactive oxygen

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species (ROS). Although ROS are essential mediators of various physiological processes, excess ROS generation can compromise normal cellular functioning by overwhelming the body’s antioxidant defense mechanism [14]. Termed oxidative stress (OS), the imbalance between oxidants and antioxidants triggers inflammatory responses and subsequently generates additional ROS to form a tissue-damaging cycle of immune overactivation. Evidence has revealed the significant involvement of ROS in allergic responses and respiratory inflammation [15, 16], which are particularly observable in allergic asthma. In this chapter, we will present a detailed outline of the pathogenesis of asthma, the role of ROS in allergic asthma, as well as the potential therapeutic treatments targeting ROS. PATHOPHYSIOLOGY OF ASTHMA Airway remodeling, AHR, and chronic airway inflammation are the most important pathophysiological characteristics of asthma (Fig. 1). It is speculated that genetics, immunity, and environmental conditions are involved in the complexity of asthma pathogenesis. Pollutants

Allergens Normal airway

Airway Inflammation  • Th2‐predominated immunity  • Eosinophilic infiltration • Airway epithelial injury Airway Remodeling • Smooth muscle  hypertrophy • Mucus secretion • Pulmonary fibrosis

Asthmatic airway

Airway Hyperresponsiveness • Bronchospasm • Epithelial nerve damage • Alteration of muscarinic  receptors composition 

Allergic Asthma

Fig. (1). An overview of three important pathophysiological characteristics that lead to allergic asthma.

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Characteristic Alterations in Asthma The fundamental pathology of bronchial asthma is airway inflammation. It is mainly induced by the exposure to exogenous factors such as allergens and chemicals, and can be highly associated with a genetic predisposition. Despite the beneficial role of inflammation in the body’s defense mechanism, chronic airway inflammation may result in complex pathological alterations, including excess mucus secretion and smooth muscle hypertrophy, which ultimately lead to airway remodeling. Along with mucus plug accumulation, airway remodeling or airway lumen thickening significantly contributes to the obstruction of airflow in asthmatic patients (Fig. 1) [17]. An autopsy report of asthmatic death reveals uniform lung inflations and apparent edema within bronchial mucus membranes. Reduced bronchial diameter due to multiple structural alterations is observable in the cross sections of primary and medium-sized bronchi. Although the pathologic characteristics differ in severity, patients with mild symptoms or at remission stage also exhibit continuous chronic airway inflammation and certain degrees of airway wall thickening. Epithelial Injury and Airway Obstruction Inflammation damages airway epithelial cells, as well as ciliated cells. The subsequent death of ciliated cells causes an alteration in the appearance, movement, and arrangement of cilia in the inner lining of bronchi. Epithelial cells may begin to shed as a result of inflammatory mediator interaction, which thereby expands the gaps between cells. On the other hand, inflammation activates goblet cell proliferation/hyperplasia and acidic protein secretion. Epithelial desquamation also contributes to the direct exposure of nerve endings. The extent of which epithelial cells are degraded by the airway inflammation is positively correlated with asthma severity. For instance, patients with mild asthmatic symptoms may exhibit slight inflammatory cell infiltration and no epithelial cell damages. However, severe asthmatic patients suffer from serious epithelial damaging and shedding, as well as mucus plug formation [18, 19]. Similarly, asthma severity is associated with increased vascular congestion and angiogenesis in the airway. The abnormal regulation of blood molecules and excessive oozing are evident in all asthmatics [20]. Bronchial biopsy of asthma patients has demonstrated an increased infiltration and proliferation of lymphatic and inflammatory cells, mainly eosinophils, mast cells, and macrophages. In fact, few lymphatic and inflammatory cells reside in the airway tissues of a healthy individual. Upon stimulation, eosinophils release toxic granular proteins such as major basic protein (MBP) and eosinophil cationic

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protein (ECP), as well as various cytokines and chemokines [5]. The degranulation of such cytotoxic proteins promotes tissue damage, induces repair mechanisms, and leads to airway remodeling [19]. Both bronchioles and bronchi of asthmatic patients are highly congested by viscous inspissated mucus and cell swelling. Mucus hypersecretion is a common response of secretory tissues to inflammation. It is likely that the hyperplasia of submucosal glands, stimulated by inflammatory mediators, elicits the buildup of viscous mucus in the airway. Particularly, the airway can be largely occluded by the formation of mucus plugs, which are lethal and can be found generally in the smaller airways, such as bronchi and bronchioles. The bronchial wall thickening due to airway smooth muscle hypertrophy further narrows airway opening and hinders breathing activities [21]. Airway Repair and Remodeling Prolonged and repeated asthma attacks may lead to irreversible structural alterations of airway since the normal wound healing process can be activated upon injury. For instance, certain growth factors and proinflammatory cytokines (e.g., TGF-) released during chronic airway inflammation are capable of inducing the differentiation of fibroblasts into myofibroblasts. The activation of fibroblasts enhances extracellular matrix (ECM) deposition, primarily collagen types I, III, and V, attributing to the thickening below the reticular basement membrane (so-called subepithelial fibrosis). In addition to the collagen deposition, non-collagenous matrix, such as fibronectin, also contributes to the thickening and stiffness of bronchus. Such remodeling via fibrosis has been reported in all severities of asthma [22]. Increased airway smooth muscle mass, which in part is mediated by the cysteinyl leukotriene from eosinophils, has been implicated in the asthmatic airway remodeling [5]. Further investigation indicates that inflammation induces a phenotypic shift in the airway smooth muscle from contractile to synthetic/proliferative. Synthetic phenotype promotes extensive ECM synthesis and perpetuates airway inflammation by secreting proinflammatory cytokines and cell adhesion molecules. The phenotypic alteration of airway smooth muscle enhances maladaptive growth and immunologic responses in asthma. Moreover, the contraction of airway smooth muscle engenders bronchoconstriction [23]. Molecular Mechanism of Airway Inflammation Cytokines are important intracellular signaling molecules that mediate the growth, differentiation, and function of various cells. The regulation of distinct cytokines

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in airway inflammation is closely associated with the type and length of the inflammatory response. The onset of chronic bronchial inflammation in asthma involves the interactions between different inflammatory cells, mainly eosinophils, chemical mediators, and airway epithelial cells. Primary inflammatory mediators include histamine, bradykinin, adenosine, and free radicals. Along with interleukins secreted by inflammatory cells and epithelial cell-derived chemokines, these mediators all function to exacerbate AHR and contribute to the characteristic patterns of asthmatic immune response [24]. The development of asthma is closely related to the deficient immune tolerance and the imbalance between T helper type 1 and 2 (Th1/Th2) cells. Such immune dysfunction alters the reactivity of Th2 cells to the environmental stimuli, leading to abnormal T cell responses and airway allergic inflammation [25]. Th1 cells mediate cellular immunity and inflammation by releasing multiple cytokines, such as interferon γ (IFN-γ), interleukin 2 (IL-2), IL-3 and tumor necrosis factor beta (TNF-β), which are protective against asthma. Th2 cells participate in the proliferation of B cells and the up-regulation of antibodies. Th2 cells produce cytokines such as IL-4, IL-5, IL-6, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF), influencing T cell differentiation and contributing to the formation of airway inflammation. The activation of Th2 cells is distinct with regards to the airway inflammation of asthma [25]. These two subtypes of T cells vary in the functions and cytokine secretion patterns, yet both serve as essential regulators of immune response. Thus, the alteration in homeostasis of Th1 and Th2 cell activity may be detrimental to the body. Th1/Th2 balance involves the complex interaction between multiple cytokines. For instance, IL-2 and IL-4 induce the differentiation and proliferation of Th1 and Th2 cells, respectively. IFN-γ diminishes the activity of IL-4. During the onset of asthma, there is a discernable decrease in the immune reaction of Th1, whereas hyperactive Th2 activity is observed [26]. Despite the importance of Th1/Th2 balance in the implication of asthma, recent studies have speculated that other factors may also account for the pathogenesis of asthma. The recently discovered Th17 cell is a novel subtype of T cells. Th17 cell produces IL-17, which is involved in the chronic inflammatory and autoimmune responses [27]. IL-17 is a powerful pro-inflammatory cytokine. It can lead to hyperexpression of IL-6 and IL-8 by activating bronchial fibroblasts, smooth muscle cells and epithelial cells, which subsequently induces neutrophil infiltration and inflammation. The study by Shi et al. has showed that Th17 and regulatory T (Treg) cells, as well as their secreted cytokines, IL-17 and IL-10, are

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largely related to asthma attacks. The action of Th17 and Treg cells are indeed antagonistic. Treg cells regulate the intensity of immune response and prevent possible tissue injury due to immune overreaction. Th17 cells mediate neutrophil migration and aggregation, activating inflammatory response that is responsible for autoimmunity [28]. Thus, the immunological imbalance between Th17 and Treg can be recognized as another factor contributing to asthma pathology. The upregulated mRNA level of IL-17 and elevated Th17 cells have been observed in the phlegm of mild/moderate asthmatic patients [29]. The mouse models of asthma also exhibit an increase in IL-17 production in the pulmonary tissues. Recent studies have implicated the involvement of neutrophils in the exacerbation of asthma. Horvat et al. suggest that Chlamydial pneumoniae infection can lead to neutrophilic asthma [30]. The extent of neutrophilic inflammation is found to be positively correlated with IL-17 expression [31]. In acute onset of asthma, the activated effector T cells generate IL-17, which stimulate airway epithelial cells to produce IL-8, a strong neutrophil chemokine [32]. The infiltration of neutrophils further aggravates airway inflammation. Therefore, IL-17 is considered as a mediator of neutrophil-induced inflammation in T cell immunity. The inhibitory effect exerted by Treg cells, through cell junctions or the secretion of cytokines (e.g., IL-10 and TGF-β), is the most effective mechanism of immune tolerance [33]. Treg cells are capable of inhibiting airway inflammation and hyperresponsiveness by mediating IL-10 [34]. Moreover, Lewkowich et al. have observed a protective effect of CD4+ and CD25+ Treg cells on the house dust mite (HDM)-sensitized mice [35]. CD4+ and CD25+ Treg cells suppress the Th2-driven immune response, suggesting that the imbalance between Th1/Th2 and Treg cells play a role in the successful development of allergic asthma [36]. Molecular Mechanism of Airway Hyperresponsiveness As described previously, airway epithelial cell damage is one of the pathological features of asthma. During chronic airway inflammation, the interactions between various inflammatory mediators can significantly damage airway epithelial cells. For instance, several cytokines produced by mast cells, such as histamine, prostaglandin D2 (PGD2), thromboxane A2 (TXA2) and leukotriene B4 (LTB4) induce bronchospasm and increase the permeability of bronchial mucus membranes. Eosinophil-secreted cytotoxin including ECP, serum eosinophil peroxidase (EPO), and MBP may directly damage the epithelium [37]. Epithelial injury causes shedding and reduces airway protection, allowing inhaled allergens and chemicals to reach the submucosa directly. Damaged epithelium can diminish the cleaning ability of cilia. Consequently, various allergens are not properly

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removed from the airway and continuous irritations are prompted. In addition, the exposed epithelial nerve endings greatly contribute to the AHR. The reduced relaxant factor production due to epithelial damage increases the contraction of bronchi. Most importantly, injured epithelium releases inflammatory mediators, such as nitric oxide (NO), further deteriorating inflammation [38]. Abnormal Neural Function in Airway Current studies have identified numerous neuropeptides in human airways. While inflammation may affect nerves and the regulatory mechanism of neuropeptide, the neuroendocrine system triggers neurogenic inflammation. Thus, the abnormal function of airway nerves is likely involved in the mechanism of AHR [39]. Wallukat et al. reported the presence of autoantibodies against β2-adrenergic receptors in the serum of asthmatic patients [40]. Other researchers suggest that inflammatory mediators such as free oxygen radicals and PGE2 can inhibit β2adrenergic receptor function both directly and indirectly. Certain viral and bacterial respiratory infections facilitate the overactivation of Th cells, disrupting immune balance and inducing the formation of β2-adrenergic receptor antibodies [41]. The exposing nerve ending due to epithelial shredding can agitate cholinergic muscarinic receptors thereby elevating the tension in smooth muscles. There are several subtypes of muscarinic receptors. In particular, muscarinic 3 (M3) receptor resides in the airway smooth muscles and submucosal glands. Upregulated expressions of M1 and M3 receptors have been observed in the asthmatic airway, whereas M2 receptor expressions are reduced. Such alteration of receptor numbers can induce airway smooth muscle contraction, as well as mucus production [42]. Despite the involvements of adrenergic and cholinergic nervous systems in the airway, there exists a third type of autonomous nervous system called the nonadrenergic non-cholinergic (NANC) nervous system. NANC nervous system is classified into inhibitory NANC (i-NANC) and excitatory NANC (e-NANC). A neuropeptide of i-NANC, vasoactive intestinal peptide (VIP), can stimulate airway smooth muscle relaxation. During inflammation, VIP is rapidly degenerated which contributes to the exacerbation of bronchial contraction. The eNANC neuropeptides, including substance-P (SP), neurokinin (NK), calcitonin gene related peptide (CGRP), and C fiber neuropeptide, participate in the neurogenic inflammation and AHR by increasing hemangiectasis and permeability [43].

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Mechanisms of Airway Remodeling Airway remodeling is a result of recurrent airway inflammation. This irreversible change in the airway structure contributes greatly to the airway obstruction in chronic asthmatic patients [44]. Subepithelial fibrosis, ECM deposition, airway smooth muscle hyperplasia and hypertrophy, angiogenesis, and mucus gland hyperplasia are all pathological features of airway remodeling. A series of growth factors (e.g., TGF-β1 and TGF-β2), interleukins (e.g., IL-11 and IL-6), inflammatory mediators (e.g., histamine), and matrix metalloproteinase (MMP) have been shown to contribute to the airway remodeling. For instance, leukotriene can stimulate the growth and production of airway smooth muscle, fibroblast, and endothelial cells [45]. The expression of TGF-β1 is essential to asthmatic airway remodeling. Higher levels of TGF-β1 mRNA have been observed in the airway mucosa of asthmatic patients [46]. TGF-β1 is considered a contributing factor of proliferative fibrosis and promotes the production of fibronectin and collagen [47]. In addition, TGF-β1 suppresses MMP and increases accumulation of ECM. Interestingly, Th17 cells and their cytokine, IL-17, are also involved in asthmatic airway remodeling. The antagonist to IL-17 acts to reduce mucus secretion, airway wall thickness and collagen deposition [48]. Recently, efforts have been put into investigating the role of myofibroblasts in asthmatic airway remodeling. Myofibroblasts are distinct cells that possess the characteristics of both fibroblasts and smooth muscle cells. Its ability to synthesize ECM is approximately four or five times more effective than fibroblasts [49]. Compared to patients with mild asthma, the number of myofibroblasts is significantly higher in refractory asthmatic patients, which is highly associated with collagen deposition [50]. Additionally, myofibroblasts can mimic inflammatory cells and generate a variety of cytokines, growth factors and inflammatory mediators. The damage and proliferation of airway smooth muscles are typical pathological features of airway remodeling [51]. Besides the involvement in the chronic airway remodeling, airway smooth muscle is essential for causing airway spasms during acute asthma. Signaling Pathways in Asthma Several signal transduction pathways are involved in the pathogenesis of asthma. First of all, GATA-3 transcription factor is a key regulator of T cell development. The activated GATA-3 induces downstream Th2 cell differentiation, thereby increasing the expression of IL-4 and IL-5. In T cells, GATA-3 promotes signal

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transducers and activators of transcription 6 (STAT6), leading to Th2 cell differentiation [52]. An overexpression of GATA-3 has been observed in patients with asthma. In a mouse model of asthma, the elimination of GATA-3 greatly reduces Th2 cytokine synthesis as well as Th2-mediated airway inflammation [53]. JAK-STAT signaling pathway is responsible for the participation of various cytokines and chemokines in asthmatic airway inflammation. It is suggested that the JAK-STAT pathway may also be involved in Th1/Th2 imbalance and immunoglobulin E (IgE) synthesis [54]. Mitogen-activated protein kinase (MAPK/ERK) pathway is closely related to the normal physiological processes of cells, which include growth, differentiation, and apoptosis. Studies have indicated an upregulation of ERK in animal models of asthma [55]. MAPK pathway may be correlated to the clinical severity of asthma [56]. Both MAPK and PI3K signaling pathways can regulate the proliferation of airway smooth muscle cells [57], which are important in the process of AHR and airway remodeling. Furthermore, the importance of nuclear factor B (NF-B) pathway has been implicated in various allergic airway diseases, as well as inflammatory diseases. It is suggested that the activation of NF-B, via IB kinase (IKK) phosphorylation, is associated with tumor necrosis factor alpha (TNF-α) and IL-1-mediated inflammation [58, 59]. Enhanced NF-B activity is observed in the lung extracts of ovalbumin-sensitized, allergic asthma rat model, indicating the essential role of NF-B in asthma pathogenesis [60]. Intriguingly, mice that lacked NF-κB family members (e.g., cRel subunit) were free from allergic development [61]. The expression of NF-κB and IKK drives the asthmatic progressions with AHR and smooth muscle thickening in the bronchial epithelium. Moreover, NF-κB activation is partly redox-regulated, yet the specific mechanism remains elusive [61]. Genetic Factors and Asthma As a common phenotype of asthma, allergic asthma can be identified clinically by two unique criteria, the presence of sensitization towards environmental allergens and the allergen-induced symptoms due to exposure [62]. Although the onset of allergic asthma may occur in all age groups, it is more likely to be observed in younger people who are associated with genetic predisposition of atopic diseases or a family history of allergic diseases [6, 62]. The development of asthma is generally regarded as the interactions between genetic and environmental factors, starting as early as in utero. Asthma demonstrates distinguishing features of familial aggregations. Indeed, substantial research has revealed the genetic relevance in asthma development. Most patients with allergic asthma experience

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consistent production of excessive IgE upon the exposure of allergens. Approximately 60% of the asthmatic children have a history of allergies or live in a population with higher consanguineous marriage rate. Moreover, asthma incidences are more common in monozygotic twins compared to dizygotic twins. Further investigation reveals a significant amount of IgE in the serum of monozygotic twins [63]. The majority of scholars believe that bronchial asthma is a complicated genetic disorder that often occurs among populations with genetic susceptibility. In addition, it is closely related to the interaction between genes, as well as the environmental factors. Cookson et al. [64] have located several asthma genes on the 11th chromosome. The genes for EceRlβ and CD20 on the 11th chromosome regulate the reactivity of IgE. The polymorphism of β2-adrenergic receptors [65] is also influential on asthma in which the missense mutation of genes coding for β2-adrenergic receptors can greatly affect the development of asthma phenotypes and airway reactivity. AHR is closely related to total IgE production, and many have located the gene for AHR on chromosomes 5q and 11q. Moreover, ADAM33 gene encodes a type of MMPs, which is responsible for airway epithelial cell repair after injury. Repetitive injury on epithelial cells can induce the overexpression of ADAM33 gene, leading to abnormal repairing mechanism and subsequent airway remodeling [66]. DIAGNOSIS OF ASTHMA Global Initiative for Asthma (GINA) has described several criteria for asthma diagnosis [6]. As previously introduced, common symptoms of asthma include recurrent wheezing, shortness of breath, and chest tightness. These symptoms are mostly induced by the exposure of allergens, cold air, chemical stimuli, upper respiratory tract infection, or exercise. Such physical signs can be relieved spontaneously or via treatment. The physicians should be always cautious when making a diagnosis of asthma, especially for special population such as children and obese patients. For example, respiratory symptoms often presented in obese subjects are quite similar to some of asthmatics [6]. Those with non-typical clinical features (e.g., without obvious wheezing or physical signs), at least one of the following examinations should be tested positive. These include bronchial provocation or exercise challenge test, bronchodilation test, and diurnal variation of peak expiratory flow within one day. Additionally, pulmonary function determination is a useful auxiliary diagnostic method for patients with atypical clinical feature. During an asthma attack, the lung function is subjected to airflow obstruction. Forced vital capacity (FVC), forced expiratory volume at the end of

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one second (FEV1), maximal mid-expiratory flow rate, and forced mid-/endexpiratory flow rate are significantly reduced. This airflow obstruction is reversible and variable. Currently, methacholine or histamine challenge tests are relatively sensitive tests for asthma diagnosis. The results provide good correlations with patients’ allergic history and clinical symptoms. Laboratory Examination for Auxiliary Diagnosis Eosinophil and neutrophil counts in the sputum can be used to evaluate asthmarelated airway inflammation, which helps select the optimal therapeutic regimen. In addition, myeloperoxidase (MPO) tests assist in the diagnosis of atypical asthma. Allergen skin prick test or serum specific antibody (IgE) determination can verify specific allergic reactions in asthma patients [67]. Additionally, the concentration determination of the expiratory gas composition such as NO can be considered as a noninvasive marker of the airway inflammation in asthma diagnosis. The expiratory NO gas is primarily generated from airway epithelial cells and macrophages [68]. It has been found that the level of fractional exhaled nitric oxide (FeNO) can reflect airway inflammation, particularly eosinophilinduced inflammation [69, 70]. FeNO is significantly correlated to AHR [71]. Notably, FeNO can serve as a predictor of acute asthma attack. Due to the convenience, efficiency, and accurate indication of airway inflammation, FeNO has become a monitoring index in the course of bronchial asthma treatment [72]. However, the potential risks for trauma has limited its application in the clinical setting. Asthma Management and Approach Patients with asthma are constantly monitored for their symptoms. In general, medications are commonly applied as a long-term asthma treatment, which have yielded favorable therapeutic effects [6]. Moreover, avoiding exposure to any possible allergens, irritated risk factors, and smoking cessation advice is fundamental to the treatment of asthma. Airway inflammation is presented in all stages of asthma. It is considered a common characteristic of all phenotypes of asthma. Although asthma remains incurable so far, its management focusing on inflammatory reduction can effectively control the clinical symptoms. There are a few principles regarding approaches on asthma medication. First, since asthma is characterized by airway inflammation, the alleviation of inflammation is indispensable. Secondly, establishing a graded therapy is necessary to effectively manage asthma with

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minimal medication. Lastly, it is essential to develop a personalized treatment based on different clinical phenotypes and characteristics [73]. The following sections introduce several asthma medications and therapies, and a summary is present in Table 1. Table 1. Asthma medications and other therapies. Drugs

Target

Effect

Clinical practice

Refs.

Respiratory region

Modulate Th2assoicated airway inflammation

Inhaled GCS is recommended for longterm asthma control

[6, 74]

β2-adrenergic agonists (short-acting)

Bronchial smooth muscle

Relax smooth muscle

Concerns of tolerance in long-term use

[75]

β2-adrenergic agonists (long-acting)

Bronchial smooth muscle

Relax smooth muscle

Combine with ICS to reduce asthma symptoms

[75]

Antileukotriene

Bronchial smooth muscle, mucus

Reduce asthma attack

Long-term for mild asthmatics with comorbidity of allergic rhinitis

[77]

Antihistamine

Bronchial smooth muscle, mucus

Anti-allergic effect

An adjunct to asthma treatment

[78]

Bronchial smooth muscle

Increase cAMP, enhance airway cleaning ability

Limited due to several side effects and complications

[81, 82]

Airway

Attenuate exacerbations

High efficacy; recommend for patients with poor response to ICS

[84, 85]

Th2 cytokine inhibitors

Th2 cytokines

Alleviate AHR and inflammation

Clinical effectiveness not verified

[89]

Anti-IgE antibodies (Omalizumab)

IgE

Inhibit stimulation of Type I allergy

Limited due to high cost

[93]

Airway wall

Reduce smooth muscle mass and airway obstruction

For severe or prolonged asthma that is not controlled by medications

[94]

Corticosteroids Glucocorticoids

Bronchodilators

Mediator Antagonists

PDE Isoenzyme Inhibitors Theophylline

Combination Therapies Corticosteroids + Longacting bronchodilators Immunotherapy

Bronchial Thermoplasty

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Asthma Medications Glucocorticoids (GCS) GCS are administrated via inhaled, oral, and intravenous routes. They are the most effective medications used to modulate Th2-associated airway inflammation. However, long-term use of GCS systematically may lead to undesirable side effects, such as suppression of growth development in children, osteoporosis, hypertension, muscle atrophy, and the inhibition of hypothalamic-pituitaryadrenal axis [74]. In addition, GCS activity is broad and lack of specificity [8]. Thus, its application in asthma is largely limited. However, inhaled GCS exerts a strong anti-inflammatory effect locally in the respiratory region, thereby preventing and/or minimizing side effects [74]. GINA report has suggested the use of inhaled GCS as a primary graded treatment for a long-term asthma control. Depending on the severity of asthma, different graded treatments emphasizing inhalation as primary treatment options can be substantially applied. Asthma patients are subjected to long-term and regular use of GCS via inhaled administration for the management of airway inflammation. Meanwhile, β2adrenergic agonists can be used to relieve asthma symptoms [6]. Bronchodilators β2-adrenergic agonists are effective bronchodilators. There are two types of these agonists: short-acting (lasts for four to six hours) and long-acting (lasts up to 12 hours). β2-receptor agonist acts to relax smooth muscle in the airway. The rapid duration of action (often within few minutes) and the long-lasting effect (few hours) make β2-adrenergic agonist a primary drug of choice in relieving mild to moderate symptoms of acute asthma [75]. Interestingly, other inhaled anticholinergic bronchodilators used in COPD such as tiotropium bromide are less effective in dilating bronchi compared to β2-adrenergic agonists [76]. Mediator Antagonists Leukotriene is a crucial inflammatory mediator produced during the metabolism of arachidonic acid. It exerts a strong vasoconstricting effect on human bronchial smooth muscle, which can lead to bronchial spasms. It can also stimulate mucus secretion, increase blood vessel permeability, and promote the formation of mucosal edema. Leukotriene plays an essential role in the initiation of an asthma attack. Hence, antileukotrienes have been used widely in clinical practice particularly in the long-term treatment for mild asthmatics with comorbidity of allergic rhinitis [77]. Second-generation antihistamines such as Ketotifen,

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Loratadine, Astemizole, Azelastine, and Terfenadine, are highly selective H1 receptor antagonists, eliciting powerful anti-allergic effects as well as serving as an adjunct to asthma treatment [78]. Phosphodiesterase (PDE) Isoenzyme Inhibitors Theophylline is the first-generation non-selective PDE inhibitor. The predominant effect of theophylline is to reduce the decomposition of cAMP and cGMP by increasing cAMP concentration in the smooth muscle. Other effects include stabilizing and inhibiting mast cells, basophils, neutrophils, and macrophages, enhancing the ability of cilia to filter the airway, and anti-inflammation [79]. Aminophylline is a type of theophylline that was used earliest in the clinical practice. Despite the low expense, the effective plasma concentration of aminophylline (8-20 mg/L) is proximal to its toxic plasma concentration. Indeed, the plasma concentration may be influenced by several factors, leading to a large amount of variance among patients [80]. Theophylline can induce digestive system-related symptoms including nausea and vomiting, as well as cardiovascular side effects such as tachycardia and arrhythmia. It also interacts with multiple medications, leading to more complications. As a result, the clinical usage of theophylline has certain limitations. Currently, there is an ongoing development of third-generation selective PDE isoenzyme inhibitors focusing primarily on PDE3, 4, and 5. These PDE inhibitors can reduce cardiovascular and digestive side effects that were present in the previous generations. Thirdgeneration PDE inhibitors include Olprinone (PDE3), Tibenelast (PDE4), Rolipram (PDE4), and Zaprinast (oral PDE5) [81, 82]. Combination Asthma Therapies Although monotherapy, particularly ICS, has been proven effective to most allergic asthmatics, it has no marked effect to some patients. Indeed, several studies have demonstrated the beneficial effects of combined medication therapy in improving asthma control. The combination therapy of ICS and long-acting β2 agonist (ICS/LABA) has been well recognized to reduce exacerbations in moderate or severe asthmatics [83]. It is recommended to patients who respond poorly to the ICS monotherapy during asthma management [84]. An inhalation of ICS/LABA mixture can outweigh individual or separate administrations of each drug, suggesting the potential synergistic interaction of ICS/LABA. However, the exact mechanism regarding the augmented efficacy of ICS/LABA requires further investigation. In addition, questions still remain on how to resolve the discrepancy between clinical effectiveness of ICS/LABA and uncontrolled asthma [84, 85].

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Immunotherapy Immunotherapy for asthma includes the specific immunotherapy (SIT), anti-IgE treatment, cytokine therapy, and neural excitation peptide receptor antagonists. SIT is also called desensitization therapy or hyposensitization therapy. The most common SIT involves the application of specific allergy vaccines in the desensitization treatment. It is mainly adopted in the treatments for allergic diseases such as allergic asthma and allergic rhinitis [86, 87]. Specifically, in a meta-analysis performed by Abramson et al., the results supported the therapeutic efficiency of allergen immunotherapy as an adjunct to allergic asthma [88]. Th2 cytokine inhibitors may be a feasible treatment for asthma, considering the role of Th2-produced cytokine, IL-4 and IL-5, in asthmatic inflammation. However, the clinical effectiveness of these inhibitors has not been verified [89]. TNF-α is a cytokine implicated in many chronic inflammatory diseases such as rheumatoid arthritis and ankylosing spondylitis. TNF-α is released during the degranulation of airway mastocytes and it is highly related to airway hypersensitiveness. Howarth et al. observed a higher TNF-α expression in the bronchoalveolar lavage fluid and bronchial biopsy of severe asthma patients [90]. Pulmonary overexpression of TNF-α may also induce muscle dysfunction [91]. Clinical studies indicate that anti-TNF- treatments effectively improve lung functions and decrease airway responsiveness [90, 92]. Anti-TNF- treatments also undesirably increase patients’ susceptibility to severe infection. Thus, the use of such treatment is currently limited to certain subtypes of asthma. Allergic asthma can be regarded as the IgE-induced Type I allergy. It has been suggested that there is a causal relationship between the IgE level and the status asthmatics. Omalizumab is a human recombinant monoclonal anti-IgE antibody. It can bind to IgE with high affinity, competitively inhibiting the stimulation of Type I allergy. Studies have shown that omalizumab can effectively relieve asthma symptoms and reduce exacerbations. The application of omalizumab has yielded positive results in two types of patients: persistent allergic asthmatics with poor response to ICS therapy and severe asthmatics that experience with little beneficial outcome from the hormone therapies. Despite the favorable effect of omalizumab in treating allergic asthma, its clinical application is largely limited due to the high cost [93]. Alternative Therapy Bronchial Thermoplasty (BT) The application of BT treatment targets the increased airway wall thickness in severe or prolonged asthma that is due to hyperplasia and hypertrophy of smooth

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muscle cells. BT utilizes radiofrequency energy to reduce smooth muscle mass present in the airway, thereby alleviating airway obstruction. BT is clinically recommended to patients with severe asthma whose conditions cannot be effectively controlled by regular medications [94]. BT has been shown to lower bronchial responsiveness, decrease the chances of asthma exacerbation, and improve overall life of patients with severe asthma [95]. MOLECULAR ASPECTS OF OS IN ALLERGIC ASTHMA Environmental Factors Related to Allergic Asthma Development Besides familiar allergens such as house dust mites and pets [96], other biological environmental risk factors including pollutants are also germane to the increased risk and persistence of asthma later in life [6]. Exacerbation of asthma induced by outdoor irritants is particularly evident in the modern living environment, likely due to urbanization where the ambient polluted particles are present [96-98]. Rapid population growth in the developing countries such as China and India accompanies with the increase in air pollution as well as asthma incidence [99]. In addition, asthma can be acquired directly from occupational exposure [6]. The role of airborne particulate matters/pollutants in influencing immunopathogenesis of asthma can be illustrated through the discussion of most commonly encountered inhalable particulates, diesel exhaust particles (DEPs), ozone and tobacco smoke, and their relation with OS [96, 97, 100]. Airborne particulate matter can exert a direct impact on the respiratory system since those inhalable particles can be introduced deeply into the airways during inspiration, triggering cytokines and oxidants production and leading to airway inflammation [96, 97]. Indeed, DEPs increase asthma severity by suppressing Treg function in the immune system. In addition, molecular mechanisms involving ROS can be generated upon the exposure to DEPs, ozone, and tobacco smoke [15, 98, 101]. It is recognized that ROS play an important role in the initiation of respiratory inflammation, a common feature that is observed in multiple respiratory diseases including asthma [15]. DEP-induced activation of cellular signaling pathways including MAPK pathways can be attenuated by antioxidants such as N-acetyl cysteine, further suggesting the involvement of ROS in the induction pathway. Despite the adjuvant activity of DEPs in elevating local IgE levels, OS caused by DEPs is perhaps paramount to the exacerbation of allergic airway inflammation. Moreover, the supplementation of vitamin C and E has provided certain degrees of protection against ozone [98].

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OS Manifested in Allergic Asthma In addition to ROS production in response to antigens and other exogenous sources, ROS are formed under multiple pathological and physiological conditions [102-106]. ROS can be produced as natural products of body metabolism. Acting as a signaling molecule, ROS are essential mediators of multiple cellular pathways, which are associated with various biological functions (e.g., cell growth) [15, 107]. Notably, ROS participate in the body’s defense mechanism and are generated by inflammatory cells to combat microbial/viral invasion. Other sources of ROS include mitochondria, xanthine oxidase and NADPH oxidase [107]. Generally, a redox homeostasis is maintained as the antioxidants remove excess ROS [108]. However, upon the exposure of allergens, AHR stimulates overproduction of ROS, which compromises cellular functioning and increases inflammation, thereby damaging important cellular components, such as proteins and DNA. Particularly, asthma attack is strongly correlated to the immediate generation of superoxide (O2•–). Activated CD4+ cells also contribute to the formation of ROS via the secretion of inflammatory cytokines, including IL-4, IL-5 and IL-13. In allergic asthma, OS exacerbate AHR, stimulate bronchospasm, and induce epithelial injury. Most importantly, the inactivation of superoxide dismutase (SOD) by OS can lead to severe airway obstruction and inflammation [15, 16]. In spite of asthma, ROS are implicated in the pathogenesis of other diseases, such as COPD and hypertension [109, 110]. ANTIOXIDANT THERAPY IN ALLERGIC ASTHMA Antioxidants and Related Therapy Interventions in Asthma Control In order to maintain cellular homeostasis and prevent oxidative damage, the body evolutionarily equips endogenous antioxidant mechanisms, which include enzymatic and non-enzymatic antioxidants, to eliminate excess ROS when needed. The involvement of pulmonary ROS in asthma pathology has been clearly established in current studies [15]. Indeed, the lung is highly susceptible to OSrelated damage mainly due to its constant exposure to oxygen and exogenous allergens. Allergen-induced oxidative injury has been implicated in allergic asthmatics [111]. Even though it is obvious that the modulation of OS may be effective in treating ROS-induced respiratory diseases, yet the application of antioxidant has yielded mixed results. In the following sections, we will provide a more thorough review on the antioxidants synthesized by the body, dietary antioxidants, free radical scavengers, and their specific applications in asthma control (Table 2).

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Endogenous Enzymatic Antioxidants In a myriad of endogenous enzymatic antioxidants, SOD, catalase (CAT), and glutathione peroxidase (GPX) are widely studied. SOD is an important metalloenzyme that can remove oxygen free radicals, especially O2•– by catalyzing the dismutation of O2•– to molecular oxygen (O2) [112]. Studies suggest the potential clinical implication of SOD in inflammatory diseases such as rheumatoid arthritis [113, 114]. SOD can also enhance immunity. Notably, SOD is extensively used in therapies associated with dermatology to resist UV radiation and aging. However, the clinical application of SOD has its limitations. The enzyme has a short half-life, a low stability and a high sensitivity to physical and chemical factors. Therefore, temperature and pH are essential for the enzyme to work properly. In addition, enzymes cannot be taken orally, which can be another disadvantage [115]. CAT catalyzes the decomposition of hydrogen peroxide (H2O2) into O2 and water. GPX is a selenoenzyme that eliminates H2O2 and other organic peroxide compounds. Selenium is a component of the GSH-Px enzyme system. It catalyzes the transformation of glutathione (GSH) to glutathione disulfide (GSSG) and at the same time decomposes H2O2 in order to protect the structure and function of cell membrane [116]. Antioxidant Mimetics Synthetic antioxidant mimetics (e.g., SOD mimetics) have been shown to modulate oxidative status in the airway epithelium, which provides potential therapeutic benefits to OS-related respiratory diseases such as asthma and COPD [117, 118]. For instance, glutathione peroxidase mimetic ebselen is a hypotoxic micromolecular organic compound containing selenium. It is an antioxidant that can effectively remove reactive compounds such as H2O2. Particularly, ebselen blocks the free radical-releasing chain reactions. Thus, it can be used to treat many diseases and maintain the body’s normal physiological functions. The mechanism of ebselen in human body includes its simulation of glutathione peroxidase (GPX) and its participation in the anti-oxidation process via thioredoxin reductase (TRXR) and thioredoxin (TRX) system [119]. It effectively removes peroxides and replenishes peroxiredoxins in the body, thereby potentially preventing multiple diseases. The antioxidative effects of ebselen are applied to the treatment of neurodegenerative diseases and focal cerebral ischemic injuries [120, 121]. Moreover, ebselen is shown to prevent NF-B activation and airway inflammation in allergic asthma [117]. Thiol Antioxidants Thiols such as GSH are one of the main antioxidant defenses both intracellularly and extracellularly [117]. Attempts to raise GSH levels in the lung via inhalation

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(e.g., GSH aerosol) have been shown to be beneficial and feasible in restoring oxidant-antioxidant balance [122, 123]. Alternatively, the supplementation of GSH precursor cysteine through the use of N-acetyl cysteine (NAC), a thiolcontaining compound which nonenzymatically interacts and detoxifies reactive electrophiles and free radicals, also increases GSH concentration in the lungs [124]. NAC is a natural product derived from L-arginine. It exerts its antioxidant activity via two mechanisms. First, upon absorption, NAC is deacetylated rapidly to form L-cysteine, a precursor molecule of GSH. Thus, the supplementation of NAC can promote intracellular GSH production and antioxidant ability. Secondly, as an antioxidant molecule, it can remove hydroxyl radical, H2O2, and hypochlorous acid (HOCl). Currently, NAC has been used extensively in the clinical treatments for COPD, pulmonary fibrosis, acute lung injury, severe hepatitis, hepatic failure, pancreatitis, and ethanol metabolism [125]. More recent studies have suggested a protective effect of NAC against OS both in vitro and in vivo. NAC has also shown to attenuate airway hyperreactivity and inflammation in animal models [108]. An alternative to NAC is a lysine salt of NAC, Nacystelyn (NAL). It can reduce both ROS levels and ROS-mediated inflammations in vitro. NAL has several advantages over NAC and can enhance GSH levels twice as effectively as NAC [126]. Therefore, NAL may be used to reduce OS in chronic pulmonary diseases. Non-Enzymatic, Dietary Antioxidants Vitamins Vitamins are candidates as potential ROS scavengers. Vitamin E is the most widely discussed fat soluble antioxidant that consists of several isoforms including - and -tocopherol. Generally, vitamin E removes free radicals, inhibits the production of nitrosamine, and plays an important role in increasing immunity [127, 128]. It is suggested that the absence of -tocopherol may contribute to the allergic airway inflammation [127]. Accordingly, Hoskins et al. demonstrated that prolonged supplementation of natural-source d--tocopheryl acetate ameliorates allergen-induced OS and allergic inflammation in human allergic asthmatics through the monitoring of F2-isoprostane formation, an oxidant marker, in the lung [128]. In addition, vitamin E deficiency is likely associated with enhanced OS and airway responsiveness [129]. Vitamin C, also known as ascorbic acid, is the most abundant antioxidant in the extracellular fluid in the lung. Various fruits and vegetables are dietary sources of vitamin C. Vitamin C can forage oxygen free radicals and suppress macrophage secretion of O2•–. The elimination of O2•–, hydroxyl radicals and alkyl peroxide

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radicals are achieved through the transformation of reduced ascorbic acid to oxidative/dehydrogenated ascorbic acid by losing electrons. Besides the strong antioxidant activity, vitamin C also increases the body’s immunity, prevents the production of nitrosamine, and improves the detoxification functions of the liver cytochrome system [130, 131]. The Third National Health and Nutrition Examination Survey (NHANES III) examined a randomized national population of the United States to explore the association between asthma risk and the alteration in serum vitamin C. They have found that an increase of 0.43 mg/dl vitamin C intake is correlated to a decrease of 13 percent in asthma incidence [130]. In addition, certain reviews have concluded that vitamin C supplementation provides a short-term benefit in treating asthma. However, there are reports that suggested no apparent relationship between asthma and vitamin C. Such deviation may be explained by the different patterns of excretion or metabolism of vitamin C among asthma subjects. Evidently, increased levels of OS due to inflammation lead to lower levels of vitamin C in serum [130]. As one of the 13 vitamins required by the body, vitamin A also demonstrates antioxidant ability through the neutralization of harmful free radicals. It is commonly known to maintain vision by facilitating the formation of photopigments. In addition, vitamin A improves the body’s immunity against contagions, such as respiratory tract infections (RTI) and parasitic infections [132]. Vitamin A derivatives may influence the development, differentiation, regeneration, and maintenance of lung epithelial cells and play an important role in the pathogenesis of airway diseases. It was found in a case-control study involving 35 asthmatic children and 29 control subjects that vitamin A deficiency was four times more common in children with severe persistent asthma. In addition, children who were supplied with oral supplementation of vitamin A for two months have shown a lower incidence of asthmatic symptoms compared to the control. Despite the potential benefits of vitamin A, there remains a controversy over the effect of vitamin A in asthma [133]. A study has found that there is no observable difference in antioxidant/micronutrient levels in plasma/serum between asthmatic patients and healthy subjects [134]. Carotenoids Carotenoids are the generic term of a group of important natural pigments, and these molecules are widely present in the yellow, orange or red forms in a range of animals, higher plants, fungi, and algae. Carotenoids are mainly categorized into three groups: carotene, lutein, and carotenoic acid. Carotenes are hydroxyl compounds. The most common representations of carotenes are

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lycopene and α, β, γ-carotene. Lutein is a nonacidic oxygen derivative of carotenoids. Carotenoic acid is actually the carboxylic acid derivative of carotene, including crocin, bixin, and torularhodin [135]. Carotenoids have excellent effects in anti-oxidation, anti-aging, and blood lipid regulation. They can largely improve the function of vascular systems, possibly by preventing cardiovascular diseases such as atherosclerosis, Alzheimer’s disease, spinal cord injury, Parkinson’s disease, and age-related macular-degeneration [136]. Carotenoids can remove carcinogenic free radicals, thereby reducing nucleic acid damage and inhibiting gene mutations. Various clinical adjuvant therapies have included carotenoid in order to enhance antibody reactions and humoral immunity [137]. As a potent antioxidant, it is suggested that carotenoids may provide protection against asthma through alleviating OS-induced damage. Low levels of carotenoids have been shown to associate with an increased risk of asthma development [138]. In a study comparing the circulating and airway levels of carotenoids in asthma and healthy individuals, the total carotenoids of asthmatic patients were significantly lower than controls. Such disturbed carotenoid status may indicate an essential role of carotenoid in asthma pathogenesis [138]. Moreover, NHANES III reported that an increase of 2.85 µg/dl in serum αcarotene can reduce the risk of asthma attack by 15 percent [130]. Flavonoids/Polyphenols Flavonoids are bioactive polyphenolic compounds that exhibit marked antiinflammatory activity [139]. Their working mechanisms include reacting with O2•– to prevent the free radical formation and chelating with metal ions to inhibit the hydroxyl radical formation. Flavonoids also react with lipid to prevent peroxidation [140]. Various flavonoid compounds extracted from plants have been applied to clinical settings, such as rutin, mangiferin, and dragonhead glucoside. The ginkgo biloba extract (GBE), which contains the main effective compound, flavonoid, has been already used in the medication and food industries. GBE has demonstrated multiple positive effects in the treatment of cardiovascular diseases, cerebral circulation insufficiency and early neural degenerative diseases [141, 142]. Moreover, GBE has been shown to reduce inflammatory cell infiltration and inflammation in the asthmatic airway, which can be used as an adjunct to GCS therapy [143]. Common dietary flavonoids, including oligomeric proanthocyanidins (OPC) and catechin, are found pervasively in plants. Numerous studies have shown that OPC are strong antioxidants. OPC are extracted from grape seeds or costal pine bark, with a stronger antioxidant capacity than both Vitamin E and C, i.e.,

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approximately 50 times higher than vitamin E and 20 times that of vitamin C [144]. In addition, OPC can be absorbed by the body rapidly. OPC concentration can reach their highest level in the bloodstream within 20 min of oral administration, and the half-life of OPC lasts up to seven hours. OPC effectively scavenge excess ROS in the body, protecting cells from oxidative injuries. There are also multiple pharmacological benefits associated with OPC, with great clinical values as described such as: OPC can improve blood circulation and vision; as well as exerts anti-angiocardiopathy, anti-radiation, anti-aging, antitiredness effects, and treats diabetic retinopathy [145]. Catechin is a main component of tea polyphenol extracts from the leaves of green tea. The effectiveness of catechin in ROS scavenging has been verified in experiments of both in vitro and in vivo [146]. Catechin can be used to treat cardiovascular, cerebrovascular diseases as well as diabetes through its ability to resist atherosclerosis, tumor growth, bacteria and viruses. Studies have also indicated that catechin increases oxygen and blood supply by enhancing SOD activity and diminishing lipid peroxidation. Therefore, it may be a potential therapeutic for coronary artery disease and hypertension [147]. Additionally, resveratrol is an antioxidant that is found in a variety of sources including grapes, red wine, moraceae plants and peanuts, functioning as a potential antimutagenic and antineoplastic agent [148]. Pharmacological ROS Scavengers Trace-Elements Likewise, multiple trace elements participate in the process of ROS scavenging. For instance, selenium is essential for the activity of both GPX and SOD. Zinc (Zn) can reduce the entering of iron (Fe) ions into the cell thereby inhibiting its catalytic activity on the ROS-induced chain reaction. In addition, the membranestabilizing action of Zn suppresses the generation of ROS by lipid peroxidation, further lessening membrane injuries [149, 150]. Copper (Cu) resides in the active site of Cu,Zn-SOD. The Cu-containing protein, ceruloplasmin, is an important antioxidant in the extracellular fluid. It mainly acts to prevent catalytic activity of Fe2+ and Cu2+, and the formation of hydroxyl radicals in the reaction associated with H2O2 [151]. Likewise, CAT is a Fe-containing enzyme and requires Fe for proper functioning. Manganese (Mn) is a component of multiple endogenous enzymes, also relating to their catalytic activities. SOD contains Mn and Cu, the two essential molecules involved in the scavenging of superoxide and enhancement of immune system [152].

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Ubiquinone Ubiquinone is a type of quinonoid. It is present in animals and plants in nature and can participate in the organisms’ redox processes. Ubiquinone is more commonly known as coenzyme Q, or CoQ. Humans can obtain ubiquinones both via synthesis and from diet. Among several ubiquinones, coenzyme Q10 is mainly present in the tissues of liver, heart, kidney, and striated muscles [153]. It is a significant component of mitochondrial respiratory chain, participating in the generation of energy. The amount of coenzyme Q10 gradually decreases as human age. Coenzyme Q10 is the indispensable energy supplier that sustains the cardiac muscles’ activity, since the heart demands high energy to function [154]. In addition, it limits the oxidation of low-density lipoprotein (LDL), reducing the formation of atherosclerosis. Coenzyme Q10 has been shown to provide protective effects in the clinical studies of cardiovascular diseases such as myocardial infarction, and possibly play a role in the preventions of the diseases [155]. It is also included in the adjuvant therapy of congestive heart failure (CHF) [156]. Furthermore, the aging of skin is closely related to the oxidation of free radicals and the amount of coenzyme Q10 [157]. Coenzyme Q10 can suppress the expression of human skin myofibroblast collagenase, prevent the oxidative damage of DNA and delay the development of skin wrinkles. Coenzyme Q10 has considerable effects on the treatment of neurodegenerative diseases that are related to mitochondrial dysfunction and aging, such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease [158]. Metallothionein Metallothionein (MT) is a micromolecular oligopeptide rich in cysteines. It has a high affinity to various heavy metals. MT can effectively elevate the toxicity of heavy metals in the human body through aggregating heavy metals. Currently, MT is an ideal biological chelating antidote [159]. Its scavenging strength for ROS is approximately 10,000 times higher than SOD [160]. Studies have shown that MT has protective effects on the nervous system, and it participates in the repair mechanism of the central nervous system [161]. In addition, Kang et al. demonstrated the potential role of MT in the protection against cardiovascular damage, which is mainly represented by the inhibition of ischemia-reperfusion injuries [162]. Anti-inflammatory Drug Inhaled Corticosteroids (ICS) OS and antioxidant imbalance can aggravate and amplify airway inflammation. ICS are currently the most effective drugs for treating asthma, serving as the firstline drug for long-term treatment of asthma. The pharmacological effect of ICS is

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to control chronic airway inflammation, thus indirectly blocking the production of ROS. In an experiment performed by Antczak et al. [163], the effect of becolmethasone, an inhaled glucocorticoid steroid, on H2O2 level of asthmatic patients was analyzed. Topical glucocorticosteroids are highly effective in the control of asthma and are used as the primary therapy in patients with persistent symptoms. 11 out of 17 patients were given inhaled beclomethasone dipropionated 400 µg/day. As a result, ICS significantly reduced the level of H2O2 in the expired breath of asthmatic patients over a 4-week period. Table 2. Antioxidant therapy in asthma control.

Enzymatic Antioxidants

Non-enzymatic, dietary antioxidants

Pharmacological ROS Scavengers

Anti-inflammatory drug

Target/function

Effect

Ref

Antioxidant mimetics (Ebselen)

Free radicalreleasing chain reactions

Enhance antioxidative ability and stimulate GPX

[117, 119]

Thiols (NAC)

Oxidative imbalance

Promote glutathione production

[124]

Vitamins

Oxidative imbalance

Increase immunity and suppress OS

[14]

Carotenoids

Oxidative damage

Alleviate OS-induced damages

[138]

Flavonoids

Free radical formation

Inhibit O2•– and OH• formation

[140]

Polyphenol Compounds

Oxidative imbalance

Scavenge excess ROS

[145]

Trace-elements

ROS-induced chain reaction

Suppress ROS generation

[149, 150]

Ubiquinone

Mitochondria

Improve mitochondrial function

[158]

Metallothionein

Oxidative imbalance

Scavenge excess ROS

[159]

ICS

Airway inflammation

Control airway inflammation and block ROS production

[163]

Strategies to Evaluate Therapeutic Effectiveness of Redox Intervention FENO According to “An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels for clinical applications”, FENO has been used as a simple, safe, and noninvasive method to measure airway inflammation quantitatively [164]. Patients with asthma have high levels of NO in their exhaled

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breath. An upregulation of inducible nitric oxide synthase (NOS2) expression in the airway suggested a role of NO in asthma pathogenesis [165]. The field of exhaled NO measurement has developed extensively over the past 15 years. The use of chemiluminescence analyzers allowed the detection of NO in exhaled breath since early 1990s. Patients with asthma were found to have high FENO, which decreases in response to ICS treatments [166-168]. FENO predicts the likelihood of corticosteroid responsiveness. FENO can be useful in determining who might benefit from steroid treatment [169-172]. Recently, researchers have reported that the transition from poor to good control of asthma is possibly associated with greater use of FENO [173]. Peroxide Level H2O2 is elevated in the exhaled air of several diseases with pulmonary inflammation, including bronchial asthma, and thus may reflect inflammatory responses in the airways. In a study involving 66 allergic asthmatic children, increased levels of H2O2 have been detected in the exhaled breath of asthmatic children [174]. Dohlman et al. also observed elevated H2O2 levels in breath from 22 pediatric asthma patients compared to healthy controls [175]. Antiinflammatory medications can lower H2O2 concentration, further suggesting H2O2 as a promising indicator of airway inflammation. Indeed, 41 out of 66 patients who received anti-inflammatory drugs, corticosteroids, have generated less H2O2 in their respiratory tract. A large difference in H2O2 concentration is recognized between asthmatics without treatment and healthy controls [174]. 8-Isoprostane 8-isoprostane is formed during ROS-induced lipid peroxidation. Since it is relatively stable in the blood and urine, it is often used as a molecular marker of OS in asthma and COPD. Studies have shown that the concentration of 8isoprostane is elevated in the breath condensate of asthma and COPD patients and it is correlated to increased OS. 8-isoprostane can stimulate thromboxane A2 receptor and induce smooth muscle contraction [176, 177]. Moreover, a study performed by Montuschi et al. has observed gradual increase levels of 8isoprostane in the breath of patients with mild, moderate and severe asthma [177]. Eosinophil As a characteristic feature of asthma, airway eosinophilic inflammation can be detected through the measurement of eosinophil and ECP in the sputum or blood. Pizzichini et al. have observed a higher proportion of sputum/blood eosinophils

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and ECP in patients with asthma [178]. Another study also indicates the associated linkage between exhaled NO and sputum eosinophil in asthmatics. These findings confirm that exhaled NO level and sputum eosinophil counts are consistent with the degree of airway inflammation [179]. Periostin Periostin is a matricellular protein that is associated with fibrosis. The upregulation and secretion of periostin can be mediated by the recombinant cytokines such as IL4 and IL-13 in the bronchial epithelial cells or fibroblasts [180]. These cytokines can be used to monitor the expression of periostin in patients with asthma. It is suggested that periostin colocalizes with other ECM proteins, contributing to subepithelial fibrosis, an essential feature of bronchial asthma [181]. SUMMARY AND PERSPECTIVE The complexity of allergic asthma can be attributed to multiple factors such as immune imbalance and genetic predisposition, which together manifest the clinical characterizations of asthma. As a chronic inflammatory disease with AHR, asthma pathogenesis involves the overreacted airway inflammation that is triggered by the exposure of allergens and other exogenous agents. The infiltration of inflammatory cells and lymphocytes to the inflamed site evokes the overproduction of ROS. In addition, ROS agitate the airway and exacerbate inflammation, completing a vicious cycle between OS and inflammation. Such lack of oxidant-antioxidant homeostasis is implicated in the development of asthma and associated symptoms. Generally, asthma control focuses on relieving airway inflammation through the application of antiinflammatory drugs (e.g., ICS). However, recent studies have been targeted ROS/OS in the development of treatments. Although the supplementations of antioxidants, such as vitamins, are feasible, their exact effects in asthma have yielded mixed results. Therefore, further research is needed to verify the effectiveness of redox therapeutics in the clinical settings. CONFLICT OF INTEREST The author confirms that author has no conflict of interest to declare for this publication. ACKNOWLEDGEMENTS We thank Andrew Graef, Anthony Re, Alexander Ziegler, Jiayi Zheng, Zan Xu and Michael Motherwell for their assistance.

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[132] Barreto ML, Santos LM, Assis AM, et al. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 1994; 344(8917): 228-31. [133] Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Della Vecchia R, D'Orazio N. Plasma lycopene and antioxidant vitamins in asthma: the PLAVA study. J Asthma 2007; 44(6): 429-32. [134] Picado C, Deulofeu R, Lleonart R, et al. Dietary micronutrients/antioxidants and their relationship with bronchial asthma severity. Allergy 2001; 56(1): 43-9. [135] Stahl W, Sies H. Antioxidant activity of carotenoids. Mol Aspects Med 2003; 24(6): 345-51. [136] Gillissen A, Roum JH, Hoyt RF, Crystal RG. Aerosolization of superoxide dismutase. Augmentation of respiratory epithelial lining fluid antioxidant screen by aerosolization of recombinant human Cu++/Zn++ superoxide dismutase. Chest 1993; 104(3): 811-5. [137] Chew BP, Park JS. Carotenoid action on the immune response. J Nutr 2004; 134(1): 257S-61S. [138] Wood LG, Garg ML, Blake RJ, Garcia-Caraballo S, Gibson PG. Airway and circulating levels of carotenoids in asthma and healthy controls. J Am Coll Nutr 2005; 24(6): 448-55. [139] Gonzalez R, Ballester I, Lopez-Posadas R, et al. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr 2011; 51(4): 331-62. [140] Knekt P, Kumpulainen J, Jarvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 2002; 76(3): 560-8. [141] Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997; 278(16): 1327-32. [142] Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998; 55(11): 1409-15. [143] Tang Y, Xu Y, Xiong S, et al. The effect of Ginkgo Biloba extract on the expression of PKCalpha in the inflammatory cells and the level of IL-5 in induced sputum of asthmatic patients. J Huazhong Univ Sci Technolog Med Sci 2007; 27(4): 375-80. [144] Weber HA, Hodges AE, Guthrie Jr, et al. Comparison of proanthocyanidins in commercial antioxidants: grape seed and pine bark extracts. J Agric Food Chem 2007; 55(1): 148-56. [145] D'Andrea G. Pycnogenol: a blend of procyanidins with multifaceted therapeutic applications? Fitoterapia 2010; 81(7): 724-36. [146] Leung LK, Su YL, Chen RY, Zhang ZH, Huang Y, Chen ZY. Theaflavins in black tea and catechins in green tea are equally effective antioxidants. J Nutr 2001; 131(9): 2248-51. [147] Garcia V, Arts IC, Sterne JA, Thompson RL, Shaheen SO. Dietary intake of flavonoids and asthma in adults. Eur Respir J 2005; 26(3): 449-52. [148] Lee M, Kim S, Kwon OK, Oh SR, Lee HK, Ahn K. Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma. Int Immunopharmacol 2009; 9(4): 418-24. [149] Abul HT, Mathew TC, Abul F, Al-Sayer H, Dashti HM. Antioxidant enzyme level in the testes of cirrhotic rats. Nutrition 2002; 18(1): 56-9. [150] el-Kholy MS, Gas Allah MA, el-Shimi S, el-Baz F, el-Tayeb H, Abdel-Hamid MS. Zinc and copper status in children with bronchial asthma and atopic dermatitis. J Egypt Public Health Assoc 1990; 65(5-6): 657-68. [151] Dumoulin MJ, Chahine R, Atanasiu R, Nadeau R, Mateescu MA. Comparative antioxidant and cardioprotective effects of ceruloplasmin, superoxide dismutase and albumin. Arzneimittelforschung 1996; 46(9): 855-61. [152] Osredkar J, Sustar N. Copper and zinc, biological role and significance of copper/zinc imbalance. J Clinic Toxicol 2011; S3: 001. [153] Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res 2006; 40(5): 445-53. [154] Sugiyama S, Yamada K, Ozawa T. Preservation of mitochondrial respiratory function by coenzyme Q10 in aged rat skeletal muscle. Biochem Mol Biol Int 1995; 37(6): 1111-20. [155] Sarter B. Coenzyme Q10 and cardiovascular disease: a review. J Cardiovasc Nurs 2002; 16(4): 9-20. [156] Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Intern Med 2000; 132(8): 636-40. [157] Baumann L. Skin ageing and its treatment. J Pathol 2007; 211(2): 241-51. [158] Shults CW. Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 2003; 10(19): 1917-21.

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[159] Mehta A, Flora SJ. Possible role of metal redistribution, hepatotoxicity and oxidative stress in chelating agents induced hepatic and renal metallothionein in rats. Food Chem Toxicol 2001; 39(10): 1029-38. [160] Liu Y, Wu H, Kou L, et al. Two metallothionein genes in Oxya chinensis: molecular characteristics, expression patterns and roles in heavy metal stress. PLoS One 2014; 9(11): e112759. [161] Chung RS, West AK. A role for extracellular metallothioneins in CNS injury and repair. Neuroscience 2004; 123(3): 595-9. [162] Kang YJ, Li G, Saari JT. Metallothionein inhibits ischemia-reperfusion injury in mouse heart. Am J Physiol 1999; 276(3 Pt 2): H993-7. [163] Antczak A, Kurmanowska Z, Kasielski M, Nowak D. Inhaled glucocorticosteroids decrease hydrogen peroxide level in expired air condensate in asthmatic patients. Respir Med 2000; 94(5): 416-21. [164] Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Resp Crit Care 2011; 184(5): 602-15. [165] Zuo L, Koozechian MS, Chen LL. Characterization of reactive nitrogen species in allergic asthma. Ann Allergy Asthma Immunol 2014; 112(1): 18-22. [166] Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6(9): 1368-70. [167] Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Bioph Res Co 1991; 181(2): 852-7. [168] Kharitonov SA, Yates D, Robbins RA, Logansinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343(8890): 133-5. [169] Knuffman JE, Sorkness CA, Lemanske RF, et al. Phenotypic predictors of long-term response to inhaled corticosteroid and leukotriene modifier therapies in pediatric asthma. J Allergy Clin Immun 2009; 123(2): 411-6. [170] Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Resp Crit Care 2005; 172(4): 453-9. [171] Szefler SJ, Martin RJ. Lessons learned from variation in response to therapy in clinical trials. J Allergy Clin Immun 2010; 125(2): 285-92. [172] Szefler SJ, Martin RJ, King TS, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immun 2002; 109(3): 410-8. [173] Michils A, Baldassarre S, Van Muylem A. Exhaled nitric oxide and asthma control: a longitudinal study in unselected patients. Eur Respir J 2008; 31(3): 539-46. [174] Jobsis Q, Raatgeep HC, Hermans PW, de Jongste JC. Hydrogen peroxide in exhaled air is increased in stable asthmatic children. Eur Respir J 1997; 10(3): 519-21. [175] Dohlman AW, Black HR, Royall JA. Expired breath hydrogen peroxide is a marker of acute airway inflammation in pediatric patients with asthma. Am Rev Respir Dis 1993; 148(4): 955-60. [176] Kinnula VL, Ilumets H, Myllarniemi M, Sovijarvi A, Rytila P. 8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD. Eur Respir J 2007; 29(1): 51-5. [177] Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med 1999; 160(1): 216-20. [178] Pizzichini E, Pizzichini MM, Efthimiadis A, Dolovich J, Hargreave FE. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997; 99(4): 539-44. [179] Piacentini GL, Bodini A, Costella S, et al. Exhaled nitric oxide and sputum eosinophil markers of inflammation in asthmatic children. Eur Respir J 1999; 13(6): 1386-90. [180] Jia GQ, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immun 2012; 130(3): 647-54. [181] Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immun 2006; 118(1): 98-104.

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CHAPTER 3

Antioxidants as a Therapeutic Option in Inflammatory Liver Diseases with a Metabolic Origin María de Fátima Higuera-de la Tijera* and Alfredo Israel Servín-Caamaño Gastroenterology Department and Internal Medicine Department, Unit 108, “Hospital General de México, Dr. Eduardo Liceaga”, Mexico City, Mexico Abstract: The inflammatory liver diseases with a metabolic origin, such as alcoholic liver disease (ALD) and nowadays, non-alcoholic fatty liver disease (NAFLD) associated to the growing epidemic of metabolic syndrome, are two important health care problems and common causes of cirrhosis and its complications in developed countries and worldwide. The physiopathology of these conditions, importantly involves oxidative stress. In ALD, alcohol metabolism comes from oxidative and nonoxidative pathways. The oxidative pathway involves two major enzymes, alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and acetaldehyde dehydrogenase (ALDH) that transforms acetaldehyde to acetate. Acetaldehyde is a cardinal toxin involved in alcohol-related liver injury. Reduced nicotinamide dinucleotide (NADH) generated by these enzymatic reactions also contributes to harm. The oxidation of alcohol also occurs via cytochrome P450 to cause liver damage by producing reactive oxygen species (ROS) that are guilty of activating redox-sensitive transcription factors, such as nuclear factor-kappaB (NF-kB), triggering and perpetuating a pro-inflammatory status. Similarly, oxidative stress, in addition to insulin resistance, is considered as a main factor contributing to liver injury in patients with non alcoholic steatohepatitis (NASH). Recently, oxidative stress constitutes a novel and attractive target for therapy, in ALD, NAFLD and NASH.

Keywords: Alcoholic liver disease, antioxidants, inflammation, liver injury, non alcoholic fatty liver disease, non alcoholic steatohepatitis, oxidative stress, therapy. INTRODUCTION The inflammatory liver diseases with a metabolic origin are major health care problem. Alcoholic liver disease (ALD) still represents one of the most common causes of cirrhosis and its complications in developed countries [1]. On the other *Correspondence author María de Fátima Higuera-de la Tijera: Gastroenterology Department “Hospital General de México, Dr. Eduardo Liceaga”, Mexico City, Mexico; Tel/Fax: 01(55)27892000; Ext: 1358; E-mail: [email protected] Atta-ur-Rahman (Ed.) All rights reserved-© 2016 Bentham Science Publishers

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hand, nowadays in the United States as in many parts of the world, non-alcoholic fatty liver disease (NAFLD), which is closely related to the growing epidemic of metabolic syndrome, obesity and diabetes, is now recognized as the most common cause of elevated liver enzymes. [2] Within the NAFLD spectrum, only non alcoholic steatohepatitis (NASH) progresses to cirrhosis and hepatocellular carcinoma. In the following decades, if the prevalence and impact of NAFLD continue to increase, NASH will be the most common cause of advanced liver disease [3]. The physiopathology of these conditions, importantly involves oxidative stress [4, 5]. Recently, oxidative stress constitutes a novel and attractive target for therapy in patients with ALD, NAFLD and NASH. Overview: Alcoholic Liver Disease Social Impact of Alcohol Consumption Alcohol consumption is as old as the human being; historical data have shown that fermented beverages exist since the Neolithic period, (10,000 B.C.) [6]. Actually, alcohol remains a major cause of liver disease worldwide. It is estimated that for each 1-L increase in alcohol intake per capita, there is an increase in liver cirrhosis of 14% in males and 8% in females [4]. Throughout the entire world, geographic variability exists in the patterns of alcohol consumption. Failure to recognize alcoholism remains an important problem and impairs efforts at both the prevention and treatment of patients with ALD. Although the exact prevalence is unknown, in 1994, around 7.4% of adult Americans met DSM-IV criteria for the diagnosis of alcohol abuse and/or alcohol dependence. In recent years 4.65% of them met criteria for alcohol abuse and 3.81% for alcohol dependence. In 2003, 44% of all deaths from liver disease were related to alcohol consumption in American population [6]. Alcohol intake is related to 3.8% of all causes of mortality and 4.6% of disabilityadjusted life-years (DALYs) lost due to premature death. From all World Health Organization (WHO) regions, Europe presents the greatest proportion of alcohol consumption, where it is associated to 6.5% of all deaths and 11.6% of DALYs attributable to alcohol. Sex differences are well defined in Europe in terms of deaths attributable to alcohol, being 11.0% and 1.8% for men and women, respectively. The young people are widely affected and alcohol-associated mortality is over 10% and 25% of female and male youth, respectively [7]. Alcohol consumption also represents a health-care problem in Latin America and the Caribbean, in these regions, proportion of all deaths that can be attributed to

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alcohol represents 4.5%. Also, as in other regions of the World, in Latin America and the Caribbean, men are more likely to drink heavily than women [8]. According to WHO, harmful drinking can be very costly to communities and societies. The abuse of alcohol is a major global contributing factor to death, disease and injury; the abuse of alcohol results in approximately 2.5 million deaths per year, with a net loss of life of 2.25 million, even taking into account the estimated beneficial impact of low levels of alcohol use on some diseases in some population groups [9]. Alcoholic Liver Disease: Pathogenic Spectrum The spectrum of alcohol-related liver injury goes from simple steatosis to cirrhosis, but multiple stages may be present simultaneously in a given individual, it means these are not necessarily distinct stages of evolution of disease. There are three main histological stages of ALD: fatty liver or simple steatosis, alcoholic hepatitis, and chronic hepatitis with hepatic fibrosis or cirrhosis [6]. Fatty liver develops almost in 90% of individuals who drink more than 60 g/day of alcohol, but may also occur in individuals who drink less. Simple, uncomplicated fatty liver is generally asymptomatic and self limited, and may be totally reversible with abstinence after about 4-6 weeks. However, some studies have indicated that progression to fibrosis and cirrhosis occurs in 5%-15% of patients despite abstinence. In one study, continued alcohol use (> 40 g/day) increased the risk of progression to cirrhosis to 30%, and fibrosis or cirrhosis to 37% [6]. A recent study conducted in France has shown that alcohol abuse accounts for up to one third of liver fibrosis cases [10]. A condition for progress to fibrosis and cirrhosis, is the development of alcoholic steatohepatitis (ASH), this condition is characterized by parecnchymal inflammation, infiltration mainly by polimorfonuclear cells (PMN), and hepatocellular damage [7]. Also, it is known that genetic and non genetic factors modify both the individual susceptibility and the clinical course of ALD [11]. Main Pathogenic Factors Contributing to Steatosis in Alcoholic Fatty Liver The four main pathogenic factors that contribute to steatosis in ALD are: Firstly, increased generation of reduced nicotinamide dinucleotide (NADH) caused by alcohol oxidation, favoring fatty acid and triglyceride synthesis, and inhibiting mitochondrial -oxidation of fatty acids. Secondly, greater hepatic influx of free fatty acids incoming from adipose tissue, and chylomicrons derived from the absorption from the intestinal mucosa. Thirdly, ethanol-mediated inhibition of

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adenosine monophosphate activated kinase (AMPK) activity resulting in increased lipogenesis and decreased lipolysis by inhibiting peroxisome proliferating-activated receptor (PPAR) and stimulating sterol regulatory element binding protein 1c (SREBP1c). Finally, damage to mitochondria and microtubules mediated by acetaldehyde, which results in a reduction of NADH oxidation and the accumulation of very low density lipoproteins (VLDL) respectively [7]. Oxidative Stress in Alcoholic Liver Disease Alcohol Metabolism and Liver Injury It is known that acute and chronic alcohol exposure is associated with high oxidative stress. Reactive oxygen species (ROS) are free radicals derived from oxygen and highly reactive molecules. They can easily oxidize and damage DNA, proteins and unsaturated fatty acids, altering cell function [12]. Alcohol metabolism occurs through oxidative and non-oxidative pathways. Alcohol exerts direct toxicity due to its predominant metabolism in the liver associated with oxidative stress. The oxidative pathway to metabolize alcohol involves alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and acetaldehyde dehydrogenase (ALDH) that converts acetaldehyde to acetate. Acetaldehyde is considered as a cardinal toxin in alcohol-mediated liver injury, causing cellular damage, inflammation, extracellular matrix remodeling and fibrogenesis [4]. Acetaldehyde also promotes cell death by depleting the concentration of reduced glutathione (GSH), inducing lipid peroxidation, and increasing the toxic effect of free radicals. Moreover, both enzymatic reactions reduce nicotinamide dinucleotide (NAD) to its reduced form NADH. Excess of NADH causes several metabolic disorders, including inhibition of the Krebs cycle and of its fatty acid oxidation. The inhibition of fatty acids oxidation stimulates steatosis and hyperlipidemia [13]. The oxidation of alcohol also takes place in the microsomes, where oxidative stress is produced principally by the activity of the microsomal ethanol oxidizing system (MEOS) through key enzymes such as cytochrome P450 to cause tissue injury by generating ROS, such as, hydrogen peroxide and superoxide ions. Particularly, cytochrome P450 2E1 (CYP2E1) is increased several fold contributing to the lipid peroxidation associated with alcoholic liver injury. CYP2E1 also converts alcohol to acetaldehyde and assists in eliminating alcohol at high blood alcohol concentrations. ROS are guilty of activating redox-sensitive transcription factors, such as nuclear factor-kappaB (NF-B), promoting and

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perpetuating a pro-inflammatory status [4]. Also, ROS can oxidize and damage DNA, proteins and unsaturated fatty acids altering cell function [12]. Other cytochromes, such as CYP1A2 and CYP3A4 may also contribute to ethanol metabolism in the microsomes [13]. Nutritional Deficiencies and Alcohol Intake Malnutrition is commonly seen in both alcoholic and non alcoholic liver disease and has been shown to adversely affect survival. The prevalence of malnutrition in cirrhosis is as high as 65% to 90% [14]. Ethanol provides 7.1 Kcal/g. In alcoholic patients, ethanol accounts for half of the daily caloric intake. It therefore displaces normal nutrients, causing malnutrition. Secondary, malnutrition also occurs through malabsorption due to gastrointestinal complications, such as pancreatic insufficiency and impaired hepatic metabolism of nutrients. Deficiencies of several vitamins and micronutrients are common, including, folate, thiamine, vitamins A, C, D and E; also zinc and magnesium [13, 14]. Patients with ALD have reduced S-adenosyl-L-methionine (SAMe) levels that may predispose to mitochondrial GSH depletion and cell dysfunction [14].This is due to an abnormal metabolism of methionine, an amino acid, because of an abnormally low activity of the enzyme methionine adenosyltransferase (MAT), the responsible for converting methionine, in the presence of adenosine triphosphate (ATP) to SAMe. SAMe is considered as the main biological methyl donor in a large variety of metabolic reactions [15]. Also, cysteine derives from the hydrolysis of cystathionine, which is a product derived from the metabolism of methionine. Cysteine is a precursor of the synthesis of GSH, a potent antioxidant [14, 15]. There are two genes encoding MAT, MAT1A and MAT2A. MAT1A is only expressed in adult liver, it encodes a catalytic subunit 1 that organizes into dimmers (MAT III) and tetramers (MAT I). MAT2A is expressed in all tissues, including fetal liver, hepatocellular carcinoma, and in small amounts in the adult liver, it encodes a catalytic subunit 2 that associates to form MAT II. MAT I and III can maintain higher intracellular SAMe concentrations than can MAT II. Under conditions of oxidative stress, nitric oxide (NO) and ROS have shown to switch both MAT I and MAT III to an inactive conformation though Snitrosylation and oxidation of a single cysteine residue in position 121 (C-121), respectively. Contrary, in response to liver injury MAT II expression is switched on, as a consequence of this switch in MAT expression, the SAMe concentration in hepatic tissue is low. In early stages of the hepatic disease, this could be an

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initial key signal to respond to injury because this state facilitates the progression of cell division cycle and hepatocyte growth. However, in patients with chronic alcohol consumption, as well as, in cirrhotic patients of other etiologies, the progressive silencing of the expression and activity of MAT I and MAT III caused by the chronicity of this condition may expose the liver to an additional oxidative stress that will favor the progression of the disease and development of complications. On the other hand, there is evidence that the inactivation of MAT I and MAT III by NO or ROS can be reversed by physiologic (millimolar) concentrations of GSH [15]. Relationship between Inflammation

Reactive

Oxygen

Species,

Kupffer

Cells

and

The activation of Kupffer cells (KCs) has a central role in the initiation of alcoholinduced hepatic inflammation. Many are the factors that contribute to activation of KCs, such as alcohol and its metabolites, endotoxin, hepatic iron overload, and of course ROS [12]. As we commented previously, during ethanol metabolism CYP2E1 and reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) are important sources of ROS. CYP2E1, a major enzymatic pathway for alcohol metabolism, is induced by ethanol not only in hepatocytes but also in KCs. Moreover, KCs and neutrophiles are the main hepatic source of NADPH oxidase [12]. Interestingly, Knecht KT, et al. found that KCs destruction by gadolinium chloride markedly reduced free radical production in the liver of alcoholic rats [16]. Furthermore, NF-B activation seems to depend on hydrogen peroxide formation [17]. NF-B is a transcriptional regulator of genes involved in immunity, cell fate, and function, and also is an essential regulator of inflammation [18]. In acute and chronic alcohol exposure, another source of ROS is derived from gut. Ethanol not only is metabolized by the liver, it can also be metabolized by bacterial and colon mucosa ADH generating acetaldehyde. Gut microbiota is the major source of lipopolysaccharide (LPS). Acetaldehyde and ROS induce gut barrier dysfunction favoring LPS derivate translocation into the portal blood to reach the liver. Bacterial LPS activates KCs through toll like receptor-4 (TLR4) pathway and favors activation of NF-B, key factor for inflammation. Alcoholinduced ROS also enhance inflammatory cytokine production by KCs through activation and sensitization to LPS. In summary, activated KCs release proinflammatory and also pro-fibrogenic cytokines and chemokines, like tumor

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necrosis factor-alpha (TNF-, interleukin-1 (IL-1), IL-6, IL-8, IL-10, and transforming growth factor- (TGF-) [12, 19]. Fibrosis in Alcoholic Liver Disease: Role of Oxidative Stress Any chronic perturbation of hepatic homeostasis may elicit the signals necessary to stimulate fibrogenesis [20]. In ALD, the development of ASH, characterized by fat accumulation and inflammation, is a cardinal element of liver injury that precedes the development of fibrosis, but also has the potential to progress into more severe pathologic states such cirrhosis, and hepatocellular carcinoma [21]. Oxidative stress has an important role in the fibrogenic process. Acetaldehyde and ROS generated by hepatic alcohol metabolism activate the production of collagen and TGF-β1 in hepatic stellate cells (HSCs) through a paracrine mechanism [22, 23]. The classic pathway of ROS generation in hepatocytes results from induction of CYP2E1 leading to pericentral injury [20]. NADPH oxidase has been recognized as another important supply of oxidative stress that mediates pathways of fibrogenic activation in HSCs, as well as in KCs. Animals genetically lacking the p47 subunit of NADPH oxidase have reduced superoxide production and attenuated hepatic fibrosis after injury, therefore, NADPH oxidase may also mediate liver injury and fibrogenesis through angiotensin signaling. Nitrosative stress could also contribute to liver fibrosis. Nitrosative stress is generated by hepatocyte mitochondrial injury and induction of NO synthase; nevertheless, links from this pathway to fibrogenesis are not completely clarified [20]. Hepatocyte apoptotic bodies induced by alcohol are phagocytosed in KCs resulting in the production of TGF-β1 and subsequently activating HSCs [24, 25]. But also, apoptosis of parenchymal cells is an important inflammatory stimulus that directly activates HSCs, which become able to phagocytose apoptotic bodies, leading to induction of NADPH oxidase. This response to apoptotic hepatocytes partially reflects the interaction of hepatocyte DNA with Toll-like receptor 9 (TLR9) expressed on HSCs. A profibrogenic response can also be raised by hepatocyte apoptosis after disruption of the anti-apoptotic mediator Bcl-xL, and by Fas [20]. Recent studies have inferred the possibility that chronic alcohol consumption predisposes natural killer (NK) and natural killer T (NKT) cells to decrease in function, which accelerates the development of liver fibrosis [26, 27].

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Overview: Non Alcoholic Fatty Liver Disease and Non Alcoholic Steatohepatitis The definition of NAFLD demands the evidence of liver steatosis, either by imaging or by histology and the exclusion of secondary causes which explain liver fat accumulation, such as significant alcohol intake, use of steatogenic drugs or hereditary diseases. Generally, NAFLD is associated with components of the metabolic syndrome such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically classified as nonalcoholic fatty liver (NAFL) or NASH. NAFL is defined by the presence of liver steatosis but without evidence of hepatocellular injury in the form of ballooning. On the other hand, NASH required the presence of liver steatosis accompanied by inflammatory infiltrate with hepatocyte injury in the form of ballooning, Mallory-Denk bodies (MDB), and with or without fibrosis [28]. Patients with NAFL have a very slow histological progression, while patients with NASH can present histological progression to cirrhosis [3, 29]. NASH also represents a risk factor for development of hepatocarcinoma, but this risk seems to be limited to those with advanced fibrosis and cirrhosis [30-32]. Some authors have estimated that near to 40% of patients with NAFLD, may develop NASH [33-35]. Nearly, 20% of those patients with NASH progress to end-stage liver disease [36, 37]. The prevalence of NAFLD in industrialized countries is estimated between 4050%, with even higher prevalence rates in patients with type 2 diabetes, and as high as 90% in the morbid obese [38]. Factors associated with disease progression include obesity and components of the metabolic syndrome, such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes. In a recent analysis by Ortiz-Lopez et al. the presence of type 2 diabetes was associated with more insulin resistance and worse histology in patients with NASH [39]. Advanced fibrosis is associated with obesity, insulin resistance, hepatocyte lipotoxicity, hyperinsulinemia, and abnormal glucose metabolism [40]. There is a close relationship between NAFLD and diabetes. Studies have been demonstrated that in the general population, elevated liver aminotransferases are associated with a greater risk of having type 2 diabetes [41, 42]. Interestingly, the majority of patients with type 2 diabetes that have fatty liver or simple steatosis and may have 50% or more may have NASH [38].

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Ortiz-Lopez et al. have been described that about 70% of patients with NASH had an abnormal glucose metabolism, either impaired fasting glucose, impaired glucose tolerance or type 2 diabetes, when they were systematically screened with an oral glucose tolerance test [40]. The presence of fatty liver in patients with type 2 diabetes is also associated with higher insulin requirements and a poorer control of diabetes [43]. Furthermore, patients with type 2 diabetes and NASH have more severe hepatic insulin resistance and are at greater risk of progressive liver disease [44]. Cardiovascular Risk in Patients with NAFLD The absolute proportion of patients with NAFLD dying from cardiovascular events increases from 3.8% within 8 years of NAFLD diagnosis to about 12% within 20 years of NAFLD diagnosis. The mortality rate of NAFLD patients is higher than in the general population. In four large series which evaluated patients with NAFLD confirmed by imaging or liver biopsy, the first or second most frequent cause of death were cardiovascular events [36, 37, 45, 46]. A frequent finding in overweight and obese people is dysfunctional insulin-resistant adipose tissue; it leads to excessive free fatty acids (FFAs) that are able to get into the liver. This promotes triglyceride accumulation, hepatocyte lipotoxicity with necrosis, inflammation and eventually fibrosis. Clinically, there are metabolic consequences such as dyslipidemia, hyperglycemia, hyperinsulinemia and low-grade inflammation; all these are considered risk factors for premature cardiovascular disease (CVD) in patients suffering NAFLD [38]. Histopathology in NAFLD / NASH Steatosis In NAFLD, the predominant type is macrovesicular steatosis, and in most adults, shows acinar perivenular (zone 3) predominance. This type of steatosis is characterized by intracytoplasmic large fat droplets and eccentric displacement of the nucleus. There may be a single large fat droplet or smaller fat droplets surrounding larger fat droplets. Studies have shown that up to 5.5% of the liver is lipid in otherwise normal individuals; thus, NAFLD is minimally defined as more than 5% of hepatocytes with steatosis [47]. Although zone 3 predominance of steatosis is characteristic in adults, individual cases may show irregular (nonzonal), pan-acinar distribution, and in children, periportal (zone 1) predominance [48]. Liver Cell Injury and Inflammation: NASH Histopathologically, markers of liver cell injury are hepatocyte ballooning and MDB. Hepatocyte ballooning is characterized by hepatocytes that appear swollen

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and round with reticulated cytoplasm, enlarged nuclei, and prominent nucleoli. Ballooning is the manifestation of loss of normal cytoskeletal structure [49]. The hepatocyte cytoskeleton is derived from keratins 8 and 18 (K8/18). These keratins have been shown to be decreased to absent in ballooned hepatocytes in NASH [50]; also, K8/18 immunohistochemical stains highlight aggregates in MDB. In adult NASH, ballooned hepatocytes are zone 3 predominant. In pediatric NAFLD, ballooning may be absent [48]. A study by Brunt et al. found that ballooning is associated with increased serum markers of necroinflammation [51]. The lobular inflammation is usually mild and is an important characteristic for the diagnosis of NASH. In most cases, lobular inflammation is composed of mixed chronic inflammatory cells, small KCs aggregates (microgranulomas), and occasionally, interspersed neutrophils. Neutrophils clustered around hepatocytes containing MDB are referred to as satellitosis; this is less common in NASH than in ASH. Portal inflammation is often present in NASH but is usually mild and less conspicuous than the zone 3 findings and lobular inflammation. More pronounced portal inflammation has been noted in pediatric patients. Lymphocytes predominate in portal inflammation [52]. Although apoptosis is not a defining characteristic of NASH and not required for diagnosis, individual acidophil bodies are often present. Apoptosis correlates with fibrosis and inflammatory activity [53]. Oxidative Stress in Non Alcoholic Fatty Liver Disease and Non Alcoholic Steatohepatitis Insulin resistance and oxidative stress are considered as key factors contributing to hepatic injury in patients with NASH [5, 54]. Increased levels of ROS, reactive nitrogen species (RNS) and lipid oxidation products, and decreased levels of antioxidant enzymes such as superoxide dismutase and catalase and antioxidants such as GSH, -tocopherol, lutein, zeaxanthin, lycopene and -carotene have been observed in patients with NAFLD and NASH [54]. Oxidative stress is one of the second hits believed to mediate the progression from NAFL to NASH. At low levels, ROS may activate NF-kB to induce synthesis of pro-inflammatory cytokines and death-receptor expression. When the amount of ROS overwhelms buffering capacity several deleterious conditions can occur, such as, peroxidation of membranes, generation of more free radicals, and even DNA mutations [55].

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Other pathological conditions associated to NAFLD and NASH, like type 2 diabetes and obesity, also present elevation of markers of systemic oxidative stress. Interestingly, a study with a cross-sectional design conducted by Meigs et al. [56] which included 2002 non-diabetic subjects of the community-based Framingham Offspring Study, found that systemic oxidative stress is associated with insulin resistance in individuals at average or elevated risk of diabetes even after adjusting for body mass index (BMI). The investigators measured insulin resistance with the homeostasis model and defined categorical insulin resistance as homeostasis model assessment of insulin resistance (HOMA-IR) >75th percentile. They measured oxidative stress using the ratio of urine 8-epi-prostaglandin F2 (8-epi-PGF2) to creatinine, and they used age and sex adjusted regression models to test the association of oxidative stress with insulin resistance in individuals without diabetes and among subgroups at elevated risk of diabetes. These authors found that across 8epi-PGF2/creatinine tertiles, the prevalence of insulin resistance increased (18.0, 27.5, and 29.4% for the first, second, and third tertiles, respectively; P < 0.0001), as did mean levels of HOMA-IR (3.28, 3.83, and 4.06 units; P < 0.0001). The insulin resistance-oxidative stress association was attenuated by additional adjustment for body mass index (BMI) (P < 0.06 across tertiles for insulin resistance prevalence; P < 0.004 for mean HOMA-IR). Twenty-six percent of participants were obese (BMI >30 kg/m2), 39% had metabolic syndrome, and 37% had impaired fasting glucose (IFG) (fasting glucose 5.6-6.9 mmol/l). Among 528 obese participants, respectively, insulin resistance prevalence was 41.3, 60.6, and 54.2% across 8-epiPGF22/creatinine tertiles (P < 0.005); among 781 subjects with metabolic syndrome, insulin resistance prevalence was 41.3, 56.7, and 51.7% (P < 0.0025); and among 749 subjects with IFG, insulin resistance prevalence was 39.6, 47.2, and 51.6% (P < 0.04). They demonstrated that systemic oxidative stress is associated with insulin resistance in individuals at average or elevated risk of diabetes even after adjusting for BMI. In a recent study, rats fed with the Lieber-DeCarli high-fat diet (71% of energy from fat) for 6 weeks expressed increased rates of hepatocyte apoptosis that mirrored necroinflammatory changes and oxidative stress [57]. The investigators noted higher phosphorylated Jun-N-terminal kinase (JNK) and Bax (proapoptotic protein) compared with controls. JNK activation has been shown to regulate cellular apoptosis [57-59], possibly through the regulation of the Bcl-2 family. In addition, JNK1 has been shown to promote the development of murine NASH [60]. Even when compared with other inflammatory entities, such as viral hepatitis C, patients with NAFLD have significantly higher levels of markers of lipid peroxidation like malondialdehyde [61].

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The oxidative stress in NAFLD may be triggered by hepatic triglyceride deposition, increased levels of FFAs and mitochondrial dysfunction. Excess fatty acid oxidation leads to hepatic oxidative stress, a reduced antioxidant defense ability and mitochondrial dysfunction, which consequently increase the expression of inflammatory cytokines, such as TNF-α. Thus, lipid peroxidation on the mitochondrial membrane is aggravated, leading to mitochondrial dysfunction and aggravating the liver toxicity of inflammatory factors and apoptosis [62]. Recently, a new concept to explain the pathogenesis of NASH was reported by Tilg and Moschen, called the “multi-parallel hit” hypothesis [63]. This hypothesis considers the steatosis as a part of the liver’s early adaptive response to stress, rather than as the first hit in disease progression, this hypothesis is of importance for reports which demonstrate that endoplasmic reticulum stress and cytokinemediated stress can induce steatosis as well as necroinflammation, suggests that multiple hits act together and simultaneously in the development of NASH. [64]. Narasimhan et al. [65] studied the changes in the oxidative stress levels in patients with NAFLD with or without type 2 diabetes mellitus. The oxidative stress level in patients with NAFLD and without impaired glucose tolerance, even insulin resistance, was observed to be significantly increased. Insulin resistance does not initially appear in patients with NAFLD, indicating that the function of oxidative stress is independent on the pathogenesis of NAFLD. Therefore, regulating hepatic inflammation and the oxidative stress level may have certain therapeutic effects in NAFLD [62]. Serum biomarkers of oxidative stress include lipid peroxidation products, such as thiobarbituric acid-reacting substances and oxidized low density lipoproteins (LDL) [66]. In a study, these two biomarkers were higher among patients with NASH as compared to age, gender and BMI-matched controls. In the same study, the total daily intake of vitamin E and carotenoids, known antioxidants, was not different between the NASH subjects and controls. However, the daily intake of these antioxidants by the entire cohort was much lower than recommended. A more recent study revealed that NASH patients had much lower levels of serum vitamin E and carotenoids than healthy controls [67]. Oxidative Stress as a Target for Therapy in ALD, NAFLD and NASH As we comment previously, oxidative stress plays an important role in the pathogenesis of ALD, NAFLD and NASH, and it represents a real therapeutic target.

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Alcoholic Liver Disease and Therapeutic Advances Targeting Oxidative Stress With regard to ALD, severe alcoholic hepatitis (AH) constitutes a condition which has a substantially worse short-term prognosis, and its physiopathology represents the most florid manifestation of oxidative stress and hepatic inflammation [68]. Although corticosteroid treatment is the standard of care and improves survival, mortality remains high, with 35% of patients dying within six months [69]. Recently, advance on survival of patients with alcoholic hepatitis was made adding antioxidants to standard therapy with corticosteroids [70-72]. Nguyen-Khac et al. [70] compared patients with AH treated with prednisolone versus patients treated with prednisolone adding N-acetylcysteine. Although mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months, it was significantly lower at 1 month (8% vs. 24%, P = 0.006). Moreover, death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P < 0.001), a shorter prothrombin time (P < 0.001), a lower level of bilirubin at baseline (P< 0.001), and a decrease in bilirubin on day 14 (P < 0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups. The thiol group in N-acetylcysteine is able to reduce levels of free radicals. Otherwise, administration of N-acetylcysteine might reconstitute the GSH stocks of the hepatocytes. Therefore, N-acetylcysteine seems to be a potential agent for therapy in patients with AH, but further studies are needed. SAMe is a promising antioxidant that may be useful for the treatment of ALD. Studies in animals revealed that SAMe administration repaired ethanol-induced defect in mitochondrial function by increasing GSH levels in rats. SAMe administration attenuated ethanol induced liver injury in baboons. Also in rats, SAMe attenuated liver injury caused by other hepatotoxins, such as carbon tetrachloride and acetaminophen. Furthermore, exogenous SAMe administration restores SAMe and GSH levels and attenuates oxidant stress and liver injury with concomitant decrease in plasma TNF- levels. SAMe administration can also prevent chemical-induced liver tumor formation by increasing DNA methylation [73]. Mato et al. [74] performed a randomized, placebo-controlled, double-blind, multicenter, clinical trial, in which objective was to investigate the effects of SAMe therapy in patients with alcoholic liver cirrhosis. They randomized 123

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patients, 62 of them received SAMe 1200 mg/day, per mouth, and the others received placebo, the duration of treatment was 2 years. Seventy-five patients were classified as Child class A, 40 as Child class B, and 8 as Child class C. At baseline, there were not differences between groups regard to sex, age, Child class, complications of cirrhosis and liver function tests. Although the difference in the global mortality/ liver transplantation was not statistically significant (P = 0.077) between groups, authors found interestingly that it decreased from 30% in the placebo group to 16% in the SAMe group. However, when patients classified as Child class C were excluded from the analysis, the global mortality / liver transplantation was greater in the placebo group compared with SAMe group (29% vs. 12%, P = 0.025). Therefore, long-term treatment with SAMe may improve survival and delay liver transplantation; nevertheless further studies are necessary to assess the effectiveness and safety of SAMe as a therapeutic option. Betaine seems to be a promising therapy in ALD. Previous studies suggested that the hepatoprotective activity of betaine is associated with its effects on sulfur amino acid metabolism. Jung et al. [75] examined in rats the mechanism by which betaine prevents the progression of alcoholic liver injury and its therapeutic potential. Rats received a liquid ethanol diet for 6 weeks. Ethanol consumption elevated serum triglyceride and TNFα levels, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and lipid accumulation in the liver. The oxyradical scavenging capacity of the liver was reduced, and expression of cluster differentiation 14 (CD14), TNFα, ciclooxigenase-2, and inducible NO synthase was induced markedly. These ethanol-induced changes were all inhibited effectively by betaine supplementation. Hepatic SAMe, cysteine, and GSH levels, reduced in the ethanol-fed rats, were increased by betaine supplementation. MAT and cystathionine γ-lyase were induced, but cysteine dioxygenase was downregulated, which appeared to account for the increment in cysteine availability for GSH synthesis in the rats supplemented with betaine. Betaine supplementation for the final 2 weeks of ethanol intake resulted in a similar degree of hepatoprotection, revealing its potential therapeutic value in alcoholic liver. Authors concluded that the protective effects of betaine against alcoholic liver injury may be attributed to the fortification of antioxidant defense via improvement of impaired sulfur amino acid metabolism. Metadoxine (MTD), a compound based on pyridoxine-pyrrolidone carboxylate, with significant scavenging properties, is suitable for increasing reduced GSH levels, which is very important for the redox homeostasis of the liver and the whole body [76].

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MTD is approved for alcohol intoxication and is also indicated for ALD. Leggio et al. [77] conducted a retrospective study of 94 outpatients with alcohol dependence. They received MTD for alcohol intoxication and were assessed for alcohol consumption, craving [Visual Analog Scale (VAS)] and liver-related and alcohol-related biomarkers: AST, ALT, gamma-glutamyl-transpeptidase, mean corpuscular volume. Range of MTD dose was 500-2000 mg/day, with a mean dose of 1277 + 290 mg/day, and for a period of 2 to 42 days, with a mean period of 8.9 + 7.0 days. There was a significant decrease in drinks per week, even after substituting baseline drinking as follow-up data for dropouts (P