COPD Is/Is Not a Systemic Disease? [1 ed.] 9781616687229, 9781608760510

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Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. COPD Is/Is Not a Systemic Disease?, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. COPD Is/Is Not a Systemic Disease?, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

PUBLIC HEALTH IN THE 21ST CENTURY SERIES

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COPD IS/IS NOT A SYSTEMIC DISEASE?

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COPD Is/Is Not a Systemic Disease? Claudio F. Donner (Editor) 2010. ISBN: 978-1-60876-051-0

COPD Is/Is Not a Systemic Disease?, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved. COPD Is/Is Not a Systemic Disease?, Nova Science Publishers, Incorporated, 2009. ProQuest Ebook Central,

PUBLIC HEALTH IN THE 21ST CENTURY SERIES

COPD IS/IS NOT A SYSTEMIC DISEASE?

CLAUDIO F. DONNER

Copyright © 2009. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Biomedical Books New York

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Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‟ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA COPD is/is not a systemic disease? / [edited by] Claudio F. Donner. p. ; cm. Includes bibliographical references and index. ISBN:  (eBook)

1. Lungs--Diseases, Obstructive. 2. Lungs--Diseases, Obstructive--Complications. 3. Inflammation. I. Donner, C. F. (Claudio F.) [DNLM: 1. Pulmonary Disease, Chronic Obstructive--physiopathology. WF 600 C781 2009] RC776.O3C67 2009 616.2'4--dc22 2009027333

Published by Nova Science Publishers, Inc.  New York

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CONTENTS Introduction

ix

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Claudio F. Donner Chapter 1

COPD is a Systemic Disease – The Pathphysiological Basis Paolo Palange and Alice Huertas

Chapter 2

COPD is not a Systemic Disease – The Pathophysiological Basis Andrea Rossi and Sonia Khirani

13

Chapter 3

Discussion on the Pathophysiological Basis of COPD

25

Chapter 4

COPD and Systemic Inflammation: Myth or Reality? Reality William MacNee

31

Chapter 5

COPD and Systemic Inflammation: Myth or Reality? Myth Giuseppe Di Maria and Raffaele Campisi

41

Chapter 6

Discussion on COPD and Systemic Inflammation: Myth or Reality?

51

Chapter 7

Biomarkers of Systemic Involvement in Stable COPD: Do they Exist? Yes Emiel F.M. Wouters

57

Chapter 8

Chapter 9 Chapter 10 Chapter 11

Biomarkers of Systemic Inolvement in Stable COPD: Do they Exist? No Fulvio Braido, Gianluca Ferraioli, Alberto Bordo and Giorgio Walter Canonica

1

71

Discussion on Biomarkers of Systemic Involvement in Stable COPD: Do They Exist?

85

Discussion In-Depth of Topics Presented in the Morning, with a View to Reaching a Consensus or Dissensus

87

Biomarkers of Systemic Involvement in Acute Exacerbations of COPD: Is There Overwhelming Evidence? Yes 103 John Hurst

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viii Chapter 12

Chapter 13 Chapter 14

Chapter 15

Chapter 16

Chapter 17

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Chapter 18

Chapter 19

Contents Is there Evidence from Biomarkers of Systemic Involvement in COPD Exacerbations? No Antonio Anzueto Discussion on: Is There Overwhelming Evidence from Biomarkers of Systemic Involvement in COPD Exacerbations? Science at the Bedside. Is COPD a Respiratory Disease with Prominent Systemic Implications or a Systemic Disease with Pulmonary Symptoms? COPD - A Primarily Respiratory Disease with Important Systemic Consequences Bartolome R. Celli Science at the Bedside. Is COPD a Respiratory Disease with Prominent Systemic Implications or a Systemic Disease with Pulmonary Symptoms? A Case Report Richard ZuWallack Discussion on: Is COPD a Respiratory Disease with Prominent Systemic Implications or a Systemic Condition with Pulmonary Symptoms?

115

125

129

155

169

Approach to COPD: Respiratory or Systemic Treatment? Respiratory Approach Richard Casaburi

173

Approach to COPD: Respiratory or Systemic Treatment? Systemic Approach Fabrizio Luppi and Leonardo M. Fabbri

181

Discussion on the Approach to COPD: Respiratory or Systemic Treatment?

199

Chapter 20

Guidelines and Clinical Practice: Myth or Reality? - Myth Marc Miravitlles

203

Chapter 21

Guidelines and Clinical Practice: Myth or Reality? - Reality Stephen I. Rennard

215

Chapter 22

Discussion on: Guidelines and Clinical Practice: Myth or Reality?

227

Chapter 23

Discussion In-Depth of Topics Presented in the Afternoon, with a View to Reaching a Consensus or Dissensus

233

Chapter 24

Summing Up and Final Remarks Nikolaos Siafakas, and Carlo Grassi

Index

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257 263

INTRODUCTION Claudio F. Donner

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Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy

Although COPD is a major disease worldwide (5th ranked cause of mortality in industrialized countries, 6th in low-middle income countries) with a steadily increasing prevalence, and COPD-driven costs are becoming a major burden for national health services and private health insurance companies alike, there is a perplexing current uncertainty about the nature of this disease. The complex variety of phenotypes and lack of an ideal biomarker that would simplify diagnosis are just two aspects of this confusion. Even the concept of the disease itself as defined by international guidelines has recently come under fire. COPD is characterized at onset by the involvement of the lungs and bronchi, but as the disease evolves abnormalities develop in many other organs and systems - e.g. renal and hormonal abnormalities, cardiovascular and metabolic diseases, muscle wasting, osteoporosis, and anemia. The key question arises: what is the pathogenesis of these respiratory and systemic impairments? Are the pathological alterations that occur outside the respiratory system in the course of COPD a direct consequence of the lung pathology or is the lung simply the local expression of a pathological event whose origin lies in the organism as a whole (and whose nature and mechanisms we have as yet only partial knowledge of)? To try to tease out this issue, which has important implications for treatment in particular, the Expert Opinion Consensus/Dissensus Seminar “COPD is/is not a systemic disease?” took place in Venice, Italy, on 13-14 November 2008. The Seminar was conceived and organized by AIMAR (Italian Interdisciplinary Association for Research in Lung Disease) with the endorsement of the two other leading national Italian Societies for Respiratory Medicine,



Correspondence concerning this article should be addressed to: Dr. Claudio F. Donner Medical Director, Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Via Monsignor Cavigioli, 10, 28021 Borgomanero (NO), Italy. Tel. +39 0322.836718; or 846549; Fax: +39 0322.869950; E-mail: [email protected].

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Figure 1:.Scientific program of the Expert Opinion Consensus/Dissensus Seminar “COPD is/is not a systemic disease?”, Venice, November 13-14 2008.

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Introduction

xi

AIPO and SIMeR. Top international opinion leaders in the respiratory field were invited to attend as speakers, chairpersons and discussants, the aim being to bring together proponents of the two sides of the argument in a format that would allow the best opportunity for discussion and debate: two 15-minute presentations „pro‟ or „con‟ on each subject followed by 30 minutes of feedback from the floor; then a further period of discussion in the afternoon, with the aim to try and reach a final consensus or dissensus on the topic. Over the two days, there was a focus on different aspects of the question both „upstream‟ (pathophysiology and biology) and „downstream‟ (treatment and outcome assessment) (Figure 1, scientific program). The first day began with an examination of the „Pathophysiological basis‟, with Paolo Palange (Rome, Italy) presenting the pro-systemic side and Andrea Rossi (Bergamo., Italy) the non-systemic side. This was followed by a look at the role of inflammation in COPD („COPD and systemic inflammation: myth or reality?‟), with William MacNee (Edinburgh, UK) sustaining the case for, and Giuseppe Di Maria (Catania, Italy) challenging the systemic argument. The focus then shifted to biological aspects, looking at the evidence for biomarkers: first in stable COPD („Biomarkers of systemic involvement in stable COPD: do they exist?‟) with Emiel Wouters (Maastricht, The Netherlands) (paper presented by Claudio M. Sanguinetti [Rome, Italy] due to flight cancellation) presenting the case for, and Giorgio W. Canonica (Genoa, Italy) the case against; then in COPD exacerbations („Biomarkers of systemic involvement in acute exacerbations of COPD – do they exist?‟) with John Hurst (London, UK) (on behalf of Jadwiga Wedzicha) putting the case for, and Antonio Anzueto (San Antonio, USA) the case against. The second day was devoted mainly to the clinical and treatment aspects („Science at the bedside‟) starting with a Case Report and Rationale („Is COPD a respiratory disease with prominent systemic implications or a systemic condition with pulmonary symptoms?‟) presented by Richard ZuWallack (Hartford, USA) and Bartolome Celli (Boston, USA), respectively. This was followed by „Approach to COPD: respiratory or systemic treatment‟ with Richard Casaburi (Torrance, USA) arguing for the respiratory approach and Leo Fabbri (Modena, Italy) for the systemic approach. Finally, clinical practice guidelines and their relevance in the light of this current debate came under scrutiny („Guidelines and clinical practice: myth or reality?‟) with Marc Miravitlles (Barcelona, Spain) arguing for the „myth‟ side and Steve Rennard (Omaha, USA) for the „reality‟ side. Ample room was given for discussion from the floor after each presentation. After further in-depth discussion at the end of the presentations, a vote was held with a view to reaching a consensus or dissensus on the topic. The general consensus that emerged, based on the limited evidence available, was that COPD begins as a local inflammation in the lungs and this leads - through differentiated pathways yet to be fully clarified – to systemic consequences. This book presents the full proceedings of the Seminar, including all the discussions, and as such represents a Statement based on the consensus that emerged on this topic from the Venice meeting. We hope that this Statement will clarify this “hot” issue for all clinicians involved in the management of COPD.

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In: COPD Is/Is Not a Systemic Disease? Editor: Claudio F. Donner

ISBN 978-1-60876-051-0 © 2010 Nova Science Publishers, Inc.

Chapter 1

COPD IS A SYSTEMIC DISEASE – THE PATHPHYSIOLOGICAL BASIS Paolo Palange and Alice Huertas University of Rome “La Sapienza”, Roma, Italy

ABSTRACT

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Chronic obstructive pulmonary disease (COPD) has traditionally been considered a disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is well known, however, that COPD is associated to significant systemic abnormalities. Since the late „80s it is known that chronic hypoxia and hypercapnia are capable of inducing renal and hormonal abnormalities in COPD patients with chronic bronchitis (type-B). More recently evidence has been provided that a significant proportion of patients with COPD, particularly those with predominant emphysema (type-A), may experience muscle wasting, osteoporosis, anemia and reduction in circulating bone marrow progenitors. These systemic abnormalities have been attributed to an increased level of systemic inflammation (e.g., increased levels of TNF-ά and IL6). Some authors have hypothesized that systemic inflammation is due to the “spilling over” of the pulmonary inflammation into the systemic circulation. Others, who failed in demonstrating a correlation between lung and systemic inflammation, raised the question if COPD may be in fact a systemic disease. Chronic inflammation, however, may not be the only cause of the systemic effects of COPD. Recent data in humans and in animal models, based on the observation of increased levels of endothelial cells apoptosis and reduced levels of angiogenetic factors (e.g. VEGF) in the lung, in response to cigarette smoking and to oxidative stress, support the view that emphysema may be a vascular disease. Other studies support the view that pulmonary emphysema carries an autoimmune component. Based on this new evidence, it is reasonable to consider COPD,



Correspondence concerning this article should be addressed to: Prof. Paolo Palange, Dept. Clinical Medicine v.le Università 37, 00185 Rome, Italy. e-mail [email protected].

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Paolo Palange and Alice Huertas

2

and in particular emphysema, as a disease with a significant systemic component if not a systemic disease per se.

INTRODUCTION

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The American Thoracic Society and the European Respiratory Society define chronic obstructive pulmonary disease (COPD) as “a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences” [1]. It is interesting to point out how the definition of COPD has evolved including henceforth the “systemic consequences” of the disease. Many extrapulmonary effects of COPD have been indeed described for the last two decades: renal and hormonal abnormalities [2], muscle wasting [3], osteoporosis [4], anemia [5] and reduction in circulating bone marrow progenitors [6]. Although these systemic manifestations have been described in COPD patients, it is still unclear whether they represent consequences secondary to the pulmonary disorder, or whether COPD should be considered as a systemic disease. Furthermore, since COPD represents a group of pulmonary abnormalities of either airways (bronchitis) or lung parenchyma (emphysema), it is reasonable to raise a question: does the systemic involvement of the disease depend on the etiology and pathophysiology of each one of the two different COPD phenotypes?

Systemic Inflammation Among the numerous extrapulmonary effects of COPD, systemic inflammation has been widely studied and considered as an important key between the pulmonary disease and the related systemic manifestations. Many studies have reported changes in various inflammatory cells and mediators, including neutrophils, lymphocytes, acute-phase reactants and cytokines. Gan and coworkers recently performed a meta-analysis [7] reviewing all these studies, showing that systemic inflammation was present not only during exacerbations of COPD, but also during stable phases of the disease: increased numbers of leukocytes, increased levels of acute phase response proteins (C-reactive protein and fibrinogen), cytokines (IL-6) and tumor necrosis factor (TNF)- were present in the peripheral blood of COPD patients. Systemic inflammation has been implicated in the pathogenesis of the majority of the systemic effects of COPD, including weight loss [8], skeletal muscle dysfunction [9], cardiovascular diseases [10] and osteoporosis [11] although it is still controversial whether this so-called low-grade systemic inflammation represents the “spilling over” of the pulmonary inflammation into the systemic vascular bed [12] or whether it really is a systemic inflammation. Vernooy and coworkers [13] as well as Hurst and colleagues [14] failed to show a relationship between TNF- and IL-8 values in induced sputum and in plasma, suggesting that the systemic

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Pathophysiological Basis of COPD – The Pro Systemic Side

3

inflammation in COPD is not linked to the pulmonary inflammation of these patients. Although inflammation is certainly one of the major features of COPD, we still need to understand whether the local inflammation is sufficient to induce systemic effects, or whether a second hit is required. Therefore, further studies need to elucidate the origin of the systemic inflammation in COPD.

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Genetics and Epigenetics The genetic etiology of COPD is certainly in favor of considering the disease as a systemic syndrome: although smoking is considered to be the major risk factor for COPD, only 15 to 20% of smokers actually develop the clinically relevant disease [1,15]. Genetic susceptibility to COPD has been investigated in the last years and numerous canditate genes have been found to encode proteins that regulate: proteases and antiproteases (1-antitrypsin, Serpine2, 1-antichymotrypsin, 2-macroglobulin, secretory leukocyte proteinase inhibitor, matrix metalloproteinases, ADAM33, protease activated receptor-2); mucociliary clearance (cytic fibrosis transmemebrane regulator, mucins); antioxidants (microsomal epoxide hydrolase, glutathione-S-transferases, cytochrome P450, extracellular superoxide dismutase); and inflammatory mediators (TNF-, IL-11, IL-1 family). Interestingly, regions of the human matrix metalloproteases (MMP)-1 promoter required for activation by smoke have been recently defined [16]. MMP-1 promoter was shown to be a direct target of cigarette smoke in lung epithelial cells, with differences in responses of polymorphic promoters to smoke. This extensive list of canditate genes attests the relevance of the genetic pathophysiology of COPD and in particular of emphysema. Many animal models have indeed helped in defining the genes involved in the pathogenesis of this latter disorder, strongly suggesting the systemic origin of the disease. Recently, cellular senescence has also been shown in a mouse model of emphysema, where knocking-out the senescence marker-protein-30 (SMP-30), which protects against aging, leads to air space enlargement [17]. Interestingly, genes that encode proteins important for the systemic immune response have been shown to be involved in experimental models of emphysema. Mice lacking Toll-Like Receptor 4, which is activated during the innate immune response, spontaneously developed emphysema associated with an oxidative stress imbalance (increased Nox3 gene expression, a novel NAPDH oxidase, and elastin degradation) [18] but without any inflammatory infiltration of the lung parenchyma. Lung gene expression studies from end-stage COPD patients have shown that the cells present impaired mitochondrial energy metabolism and protein synthesis [19], suggesting DNA damage and post-trancriptional modifications, but little is known about epigenetic marks in respiratory diseases. Interestingly, in COPD, it has been shown that histone deacetylase (HDAC)-2 is markedly reduced in expression and activity in lung parenchyma, bronchial biopsies and alveolar macrophages, and this decrease is correlated with disease severity and the intensity of the inflammatory response [20]. Overexpression or knockdown of HDAC2 in alveolar macrophages from COPD patients affected not only the inflammatory response but also the corticosteroid responsiveness, implicating an additional role for HDAC2 in the anti-inflammatory actions of corticosteroid [21].

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Paolo Palange and Alice Huertas

The clinical impact of cigarette smoking, which ranges from negligible to end-stage lung disease, is determined in part by individual susceptibility factors. Understanding the factors that lead to emphysema is useful for predicting which individuals are at risk. Deficiency in 1-antitrypsin is one factor that results in a predisposition to smoking-induced emphysema, but despite intensive study, few other susceptibility factors are as well defined. Genetic susceptibility and epigenetic modifications strongly suggest a systemic etiology of COPD, but further data are needed to better define the precise etiolopathology of the disease.

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Vascular Abnormalities The loss of alveolar capillary endothelial cells was observed in emphysema almost 50 years ago [22] but new data have been trying to confirm the vascular nature of emphysema, suggesting a systemic involvement of the disease [23-26]. The vascular endothelial growth factor (VEGF) has played an important role in the vascular pathogenesis of COPD, but in particular in emphysema. VEGF has a fundamental role in physiological and pathophysiological forms of angiogenesis and regulation of endothelial cell differentiationas demonstrated by the lethality of VEGF knockout mice and abnormal vasculogenesis of the heart and large vessels with the loss of only a single copy of the VEGF gene [27]. VEGF, also known as vascular permeability factor (VPF) displays several key functions in the lung, such as migration and proliferation of endothelial cells, monocyte adhesion, angiogenesis, vasodilatation and enhanced permeability, as well as early hemangioblast development. But above all, a crucial role in the genesis of emphysema has been developed based on the observation that VEGFR-1 blockade of VEGFR-1 and VEGFR-2 arrests lung growth and leads to an emphysematous mouse phenotype [28]. Therefore, an interesting model of VEGFR blockade with SU5416 results in endothelial cell apoptosis causing an apoptosisdependent emphysema in rodents [29, 30]. The finding that decreased VEGF or VEGF signaling caused experimental emphysema leads to the concept that alveolar maintenance is required for structural preservation of the lung, disrupted by cigarette smoke, causing emphysema [31, 32]. Therefore, it appears quite legitimate to raise the question whether maintaining cell homeostasis by growth factors such as VEGF could rescue emphysema. Unfortunately, no data are so far available on the potential benefits of VEGF gene therapy in emphysematous lung. VEGF is a tightly regulated gene in the lung, playing specific growth and differentiation roles in different structural and cellular compartments. While VEGF protein and mRNA contents in the lung are reduced in severe emphysema, VEGF gene expression is increased in pulmonary arteries of smokers and patients with moderate COPD and correlated with medial thickening of the pulmonary vascular walls [23]. These data certainly confirm the systemic pathogenesis of emphysema, but also underlie the multifactorial aspect of the disease [33].

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Pathophysiological Basis of COPD – The Pro Systemic Side

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Immunology An interesting characteristic of emphysema is the lack of attenuation in inflammatory and disease parameters years after the cessation of smoking: tobacco smoke seems to contain antigens that induce immunological responses in susceptible individuals. But it might also be a more complex pathogenesis in which smoking induces an autoimmune response to an endogenous lung antigen. This alternative concept of the pathogenesis of emphysema has been certainly raised by Voelkel and coworkers, showing that humoral- and CD4+ cell– dependent mechanisms are sufficient to trigger the development of emphysema, suggesting that alveolar septal cell destruction might result from immune mechanisms [34]. Using a mouse model, they showed that intraperitoneal injection of endothelial cells causes emphysema, leading to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2. Furthermore, naive immunocompetent animals also developed emphysema following administration of CD4+ T cells. This hypothesis has also been investigated in humans: isolating peripheral blood CD4+ T cells from emphysema patients, Lee and coworkers were able to show that exposure to cigarette smoke induces secretion of proteolytic enzymes from cells of the innate immune system that liberate lung elastin fragments which, in susceptible individuals, could initiate T- and B-cell–mediated immunity against elastin [35]. These data strongly suggest the autoimmune pathogenesis of emphysema, characterized by the presence of antielastin antibody and T-helper type 1 (TH1) responses that correlate with emphysema severity. It is interesting to remark that since elastin is also abundant in tissues other than the lung, especially in arteries, arterioles and in the skin, in addition to emphysema, tobacco smokers are at high risk for coronary artery disease, aortic aneurysms and elastolytic changes of the skin [36, 37]. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers. Findings of antielastin autoimmunity in emphysema therefore suggest a broader, systemic autoimmune process involving the major elastinbearing organs that may explain these diverse clinical observations. On the other hand, several clinical reports have described cases of emphysema in patients with hypocompletemia, and in particular with an history of hypocomplementemic urticarial vasculitis. Although we need to better define this possible pathogenesis, these reports suggest that an impaired immunological condition could lead to the development of emphysema [38,39], underlying the systemic pattern of the disease.

Repair Failure The destruction of alveolar walls leading to the enlargement of alveolar spaces, which is the well-known hallmark of emphysema, could also be considered as the result of an impaired repair capacity. In addition to this, there are indications that lung repair, as evidenced by de novo synthesis and tissue accumulation of elastin and collagen, is inhibited by cigarette smoke [40]. Exposure to cigarette smoke extract also inhibits fibroblast proliferation [41],

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Paolo Palange and Alice Huertas

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and fibroblasts isolated from patients with emphysema exhibit decreased proliferative capacity [42, 43]. Abnormal mesenchymal repair functions have been observed in fibroblasts obtained from emphysematous human lung. Holz and colleagues demonstrated that fibroblasts cultured from lungs of patients with emphysema proliferate more slowly than fibroblasts obtained from the lungs of similarly aged individuals without emphysema [43]. Togo and Holz extended these results to demonstrate that fibroblasts from emphysematous individuals are also less capable of responding to a chemotactic stimulus and are less potent in contracting three-dimensional collagen gels [40]. It is unclear if the differences between the fibroblasts obtained from normal and emphysematous individuals represent underlying genetic differences and hence susceptibility to developing emphysema, or if they are an acquired defect. Exposure to cigarette smoke extract induces cell cycle arrest in fibroblasts, mediated through activation of p53 and p16, which inhibit the cell cycle, leading to cellular senescence [44], which may represent a response of fibroblasts to DNA damage by cigarette smoke extract [45]. This may result in abnormal wound healing and prevention of repair of lung injury. In addition, cigarette smoke can kill endothelial cells and endothelial cell precursors [46] and inhibit airway epithelial cell chemotaxis and proliferation [47].

Figure 1. CD34+ cells at baseline (BL) and after enduarance exercise (Exe) in chronic obstructive pulmonary disease (COPD) patients (●) and in control subjects (○). Note the marked uniform reduction in CD34+ cells in COPD patients compared with the control subjects. *: p