Pathogenesis of Chronic Obstructive Pulmonary Disease
Section snippets
Chronic bronchitis
Chronic bronchitis is defined as cough and sputum production for most days over 3 months for 2 consecutive years. This clinical definition does not include the presence of airflow limitation. It is thought to result from the innate immune response to inhaled toxic particles and gases, particularly in tobacco smoke. The epithelium of the central airways and the mucus-producing glands are inflamed in chronic bronchitis [3], [4]. This airway inflammation is associated with increased mucus
Inflammation in the lungs of smokers without chronic obstructive pulmonary disease
Inflammation occurs in the peripheral airways of all smokers, even before COPD is established, and is made up of inflammatory cell infiltrate in the airway wall consisting of mononuclear cells and clusters of macrophages in the respiratory bronchioles. These lesions occur initially in the absence of any significant tissue destruction or fibrosis, and may be reversible. A similar inflammatory process with T lymphocytes and macrophages has been described in the large airways of smokers [14].
Inflammation in the lungs of persons with chronic obstructive pulmonary disease
Studies of lung or bronchial biopsies and induced sputum have shown evidence of lung inflammation in all cigarette smokers [12], [18], [19]. However, it appears that an enhanced or abnormal inflammatory response to inhaling particles or gases, which goes beyond the normal protective inflammatory response in the lungs, is a characteristic feature of COPD and has the potential to produce lung injury [21]. The innate and adaptive inflammatory and immune responses are involved in the lung
Proteases/antiproteases
A large body of literature has been amassed to test the hypothesis that a protease/antiprotease imbalance, leading to the breakdown of connective tissue components, particularly elastin, is the critical mechanism in the pathogenesis of emphysema in smokers. This concept developed from studies showing the development of early-onset emphysema in patients deficient in the major ant elastase α1-AT [121] and from animal studies showing the development of emphysema in response to the instillation of
Oxidative stress
The lungs are unique compared with other organs in that they are directly exposed to high levels of oxygen. In addition, because of its direct contact with the environment, the respiratory epithelium is a major target for oxidative injury from oxidants generated either exogenously (inhaled oxidants such as cigarette smoke or air pollutants), or endogenously (from phagocytes and other cell types). As a result, the lungs require efficient enzymatic and nonenzymatic antioxidant systems to protect
Latent viral infection
Possible mechanisms related to the abnormal regulation of inflammation in COPD are shown in Fig. 7. Studies have suggested that susceptibility to COPD may be related to latent adenoviral infection (see Fig. 7). These studies have demonstrated the ability of adenoviral E1A proteins, which associate with DNA, to enhance the binding of a number of transcription factors to their nuclear consensus sites, to activate subsequently various genes [249]. The E1A protein occurs more commonly in the lungs
Summary
No single mechanism can account for the complex pathology in COPD. It is likely that interactions occur among different mechanisms, such as interactions among inflammation, protease/antiprotease imbalance, oxidative stress, and apoptosis as destructive processes in emphysema. Better understanding of the relative importance of these different pathogenic mechanisms and the processes that amplify and perpetuate them will come from proof-of-concept therapeutic intervention studies.
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Research for this article was supported by National Institutes of Health # 1 ROI HL72282–01.