Apr 7, 2009 - 1University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom; 2Department of.
Burden and Pathogenesis of Chronic Obstructive Pulmonary Disease Robert A. Stockley1, David Mannino2, and Peter J. Barnes3 1
University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom; 2Department of Preventive Medicine and Environmental Health, University of Kentucky College of Public Health, Lexington, Kentucky; and 3Imperial College London, National Heart and Lung Institute, London, United Kingdom
The burden of chronic obstructive pulmonary disease (COPD) is rising, incurring a major health care burden worldwide. There is no specific therapy other than smoking cessation, which is only partially successful. The condition is recognized to be the result of abnormal control of the inflammatory response to known risk factors, although the exact mechanisms have yet to be identified. However a1-antitrypsin deficiency represents a human model of all the components of COPD (especially emphysema), and the genetic nature allows family studies of subjects who are well or in the early stages of disease progression. Emphysema distribution has facilitated further understanding of physiologic impairment with particular reference to discordance between FEV1 and tests of gas transfer. The condition also emphasizes the role of the neutrophil in the inflammatory cascade in both deficiency and usual COPD. Deregulation and resistance of the inflammatory cytokine cascade appears to be a regular feature of usual COPD, and may represent a premature ageing phenotype. Molecular studies provide new insights that may lead to specific therapies to halt progression. Keywords: chronic obstructive pulmonary disease; inflammation; epidemiology
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity worldwide, and is one chronic disease that continues to increase in prevalence and mortality, and is projected to continue to increase into the future (1). COPD, as defined by the Global Obstructive Lung Disease (GOLD) guidelines is: . . .a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. (2)
The reality, though, is that COPD is a heterogeneous group of diseases with similar manifestation and includes disparate and overlapping disease processes such as chronic bronchitis, emphysema, asthma, bronchiectasis, and bronchiolitis.
BURDEN OF COPD The burden of COPD consists of several components, including the proportion of the population that has evidence of disease, the effect that disease has on affected individuals, and the costs to society incurred by patients with disease. Estimates of COPD
(Received in original form April 7, 2009; accepted in final form May 27, 2009) Correspondence and requests for reprints should be addressed to Robert A. Stockley, D.Sc., University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: rob.stockley@ uhb.nhs.uk Proc Am Thorac Soc Vol 6. pp 524–526, 2009 DOI: 10.1513/pats.200904-016DS Internet address: www.atsjournals.org
prevalence, defined using GOLD criteria of stage 2 or higher disease, range from 3% to 23% of the population across different countries (3). Similarly, the mortality of COPD ranges from an estimated 4.4/100,000 in Japan to 130.5/100,000 in China, and disability-adjusted life years range from 120/ 100,000 in Japan to 667/100,000 in India (3). The estimated additional annual costs for patients with COPD ranges from $1,000 to $8,000 (3).
RISK FACTORS FOR AND COMPLICATIONS OF COPD Smoking is the main risk factor for COPD. Other factors, however, are also important, including occupational and environmental exposures, genetic factors, and increased airway responsiveness (4, 5). In the developing world, exposure to both indoor and outdoor air pollutants are important in the pathogenesis of COPD. In addition, there is some evidence that early life exposures to both infectious and noninfectious agents might play an important role in the development and advancement of COPD. COPD is also a risk factor for the presence or development of other chronic illnesses, include cardiovascular disease, depression, osteoporosis, and lung cancer (6). Optimal treatment of COPD must also adequately address these other associated processes that can have a considerable impact on the lives of our patients.
PATHOPHYSIOLOGY There is no specific therapy for COPD; however, in view of the enormous health care burden, there is increasing activity into understanding the pathophysiology of COPD. The identification of plasma deficiency of a1-antitrypsin (AAT) has added greatly to our understanding of the features of COPD, with particular emphasis on the emphysematous component. The genetic nature of AAT deficiency has the advantage of family studies identifying individuals with a wide range of impairment from normal lung function to severe disease. This enables the features and progression of the disease to be studied in depth. Emphysema destruction has variable effects on lung physiology, with gas transfer being more affected than FEV1 by upper zone emphysema (7). In addition, data suggest that this is one of the earliest measures to change as lung damage progresses, preceding the FEV1 by many years. This is consistent with cross-sectional observations that emphysema is often present in usual COPD even before the FEV1 becomes abnormal. Such studies may facilitate early detection of individuals at risk. The advent of high-resolution CT scanning and its more recent use for quantifying and localizing emphysema has also added new insights to both AAT deficiency and usual COPD. The classical distribution of emphysema in AAT-deficient individuals is basal, although some patients have apical emphysema more typical of usual COPD. Physiologic studies in AATD have shown that apical emphysema correlates better
Stockley, Mannino, and Barnes: Burden and Pathogenesis of COPD
with gas transfer than FEV1 and that the opposite is true for basal disease. In studies of AATD patients with reduced gas transfer but normal FEV1, the distribution of emphysema was confirmed to be more apical and separated in distribution from subjects with reduced FEV1 and normal gas transfer (8). These data confirm the differential effects of emphysema distribution on lung function. About 50% of patients with usual COPD have emphysema, and in them the gas transfer is more impaired even in the presence of normal FEV1, raising questions about the physiologic diagnosis of COPD. AAT is the best plasma (and hence interstitial) inhibitor of serine proteinases, and deficiency results in a failure to control these enzymes when released from activated neutrophils. In particular, neutrophil elastase (NE) has long been implicated in the pathophysiology of emphysema, since it can induce this pathologic change in the lungs of exposed animals (9). However, in vivo the process is complex and involves neutrophil migration into the lung interstitium from the vasculature. During this process, NE becomes localized at the leading edge of the neutrophil and is left behind as the cell moves (10). The concentration of NE at the point of release is too high to be completely inactivated, even in subjects with normal AAT levels (11). The net result is an area of obligate proteolysis leading to tissue damage. The low levels of AAT in subjects with genetic deficiency amplifies this potential damage and hence rate of onset and progression of emphysema. The same process can be implicated in nondeficient emphysema. Tissue NE relates to the severity of pathologic emphysema (12). Further, neutrophils from such subjects have intrinsically greater migratory responses and destructive potential than normal (13). Finally, progression of emphysema on CT scan over 4 years relates to the initial markers of neutrophil migration (14) and hence the potential destructive capacity. Thus it is likely that NE plays a central role in the destructive connective tissue cascade induced by the underlying inflammation (Figure 1). However, the exact nature of inflammation and its control/ dysregulation in usual COPD is a complex process that is likely to be multifactorial.
MOLECULAR MECHANISMS OF INFLAMMATION IN COPD COPD is associated with a chronic inflammation of the airways and lung parenchyma, characterized by increased numbers of neutrophils, activated macrophages, and activated T-lymphocytes (Tc1 and Th1 cells) (15). The inflammation in COPD lungs is amplified compared with that seen in normal smokers, and the molecular mechanisms for this amplification are now better understood, providing novel targets for future therapies. Macrophages are markedly increased in COPD and these cells play a key role in recruiting other inflammatory cells (such as neutrophils) and in releasing mediators and proteases. Macrophages in the lung are recruited from circulating monocytes by chemotactic factors, such as CXCL1 and CCL2 (16). The inflammatory changes in COPD are due to the release of multiple inflammatory mediators, including lipid mediators, cytokines, and chemokines. Activated macrophages and neutrophils release elastolytic enzymes, particularly neutrophil elastase and matrix metalloproteinase-9 (MMP-9), that result in emphysema and enhanced inflammatory cell recruitment into the lungs. In addition, Tc1 cells may induce the apoptosis of Type 1 alveolar cells through the release of perforins to promote emphysema. Small airway narrowing as a result of inflammation and fibrosis appears to be a major mechanism contributing to progressive airflow limitation and air trapping, but the mechanisms of fibrosis in COPD are not yet well understood.
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Figure 1. Schematic integration of cytokine/cell/serine and metalloproteinase pathways involved in the pathophysiology of emphysema based on concepts refined in animal models and human observations.
In sharp contrast to asthma, the inflammation in COPD shows little response to corticosteroids (17). This steroid resistance may be explained by reduced activity of a key nuclear enzyme histone deacetylase-2 (HDAC2), which is required by activated glucocorticoid receptors to switch off activated inflammatory genes, and this may also account for the amplified inflammation in COPD (18). Increasing HDAC2 in COPD macrophages to normal levels using a plasmid vector results in restoration of corticosteroid responsiveness in these cells (19). HDAC2 activity and protein expression are reduced by oxidative stress through peroxynitrite-induced nitration of tyrosine residues and by phosphorylation as a result of activation of phosphoinositide-3-kinase-d (PI3K-d). Low concentrations of theophylline restore the low levels of HDAC2 levels in COPD macrophages to normal and reverse steroid resistance in vitro and in vivo by blocking PI3K-d (20). Studies such as these may lead to new therapeutic approaches with the use of low dose theophylline and, in the future, PI3K-d selective inhibitors to reverse corticosteroid resistance. Whether this influences the development and progression of COPD remains to be seen. There is growing evidence that COPD may represent accelerated ageing of the lung in response to chronic oxidative stress (21). Oxidative stress leads to the reduction of a key antiaging molecule, the sirtuin SIRT1, which is a protein deacetylase that is a key regulator of MMP-9. SIRT1 expression is markedly reduced in COPD lungs, macrophages and lungs in cigarette smoke–exposed mice, and is associated with increased MMP-9 activity, but this may be reversed by potent SIRT1 agonists in vitro and in vivo. The process remains complex, but these mechanistic pathways offer clearer understanding of the pathophysiology and hence the development of specific and effective molecular therapies. Conflict of Interest Statement: R.A.S. served as a consultant and served on the Board or Advisory Board for GlaxoSmithKline (GSK), Roche, Nycomed, and Talecris $1,001–$5,000. He received lecture fees from Talecris, GSK, and Nycomed $1,001–$5,000. He received grant support from AstraZeneca (AZ) and Talecris $100,001 or more. D.M. served as a consultant for Pfizer, GSK $10,000–$50,000, and Novartis $1,001–$5,000. He served on the Board or Advisory Board for Pfizer, GSK $10,000–$50,000, AZ, and Novartis $5,001– $10,000. He received lecture fees from Pfizer $10,001–$50,000, GSK $50,001–
526 $100,000, AZ $10,001–50,000, Dey $5,001–$10,000, and Sepracor $1,001– $5,000. He served as an expert witness for Schachman and Associates $50,001– $100,000 and received grant support from Pfizer, GSK, and Novartis $100,001 or more. He receives royalties from Up-to-Date up to $1,000. P.J.B. served on the Board or Advisory Board for AZ, Boehringer Ingelheim, Chiesi, Teva, and Novartis $1,001–$5,000. He received lecture fees from AZ $10,001–$50,000, Boehringer Ingelheim $5,001–$10,000, Teva, and Chiesi $1,001–$5,000 and served as an expert witness for Boehringer Ingelheim $5,001–$10,000 and Teva $10,001– $50,000. He received grant support from GSK, AZ $100,001 or more, Novartis, Daiichi-Sankyo, and Cempra $50,001–$100,000.
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