Pathogenesis of chronic obstructive pulmonary disease

Abstract

The current epidemic of chronic obstructive pulmonary disease (COPD) has produced a worldwide health care burden, approaching that imposed by transmittable infectious diseases. COPD is a multidimensional disease, with varied intermediate and clinical phenotypes. This Review discusses the pathogenesis of COPD, with particular focus on emphysema, based on the concept that pulmonary injury involves stages of initiation (by exposure to cigarette smoke, pollutants, and infectious agents), progression, and consolidation. Tissue damage entails complex interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death. Lung damage by cigarette smoke ultimately leads to self-propagating processes, resulting in macromolecular and structural alterations - features similar to those seen in aging.

Figures

Figure 1. Pathogenetic factors organized based on their role in the initiation, progression, and consolidation of emphysema.

(A) Initiation: Environmental agents trigger host cell responses, largely dominated by inflammation and oxidative stress. RTP801 is activated by cigarette smoke, largely due to oxidants, mediating inflammatory responses, oxidative stress, and alveolar cell death. DAMPs and PAMPs present in tobacco or generated endogenously may further enhance pathologic responses. Nrf2, by activating a host of antioxidant mediators, protects the lung and may promote lung repair processes. (B) Progression: Cigarette smoke disrupts alveolar maintenance, triggering apoptosis and autophagy; moreover, oxidants in tobacco and activated inflammatory and alveolar cells lead to extracellular matrix proteolysis, which further enhances inflammation and promote a feedback loop with apoptosis. Several of these interactions are facilitated by decreased expression of trophic/maintenance factors and endogenous mediators of alveolar destruction, including ceramide and EMAPII. (C) Consolidation: Over decades of exposure to cigarette smoke and endogenous amplifiers of destructive processes, there is progressive lung aging, with autoinflammatory stimuli generated through self-antigens or microbial/viral agents. TH17-positive cells, which are increased in COPD patients, may mediate the autoimmunity process. Macromolecular damage may lead to progressive telomere erosion and activation of p21CIP1/WAF1/SDI1 as part of the cell senescence response, which together may lead to a terminally injured lung.