Apoptotic mechanisms in the pathogenesis of COPD

Abstract

COPD is a leading cause of morbidity and mortality, characterized by a chronic abnormal inflammatory response to noxious agents. Apoptosis is a physiologic process, critical to cellular homeostasis, in which cell death follows a programmed sequence of events. Apoptosis has been recognized to play an important role in clinical and experimental models of lung diseases. Abnormal apoptotic events in smokers' and in emphysematous lungs have been shown in epithelial and endotheliallung cells, neutrophils, lymphocytes, and myocytes. Many factors associated with COPD, including cigarette smoke, have the potential to cause apoptosis of alveolar epithelial cells, the main sites of vascular endothelial growth factor (VEGF) production. The decreased expression of VEGF, a known survival factor for endothelial cells, and its receptor, results in lung septal endothelial cell death, leading perhaps to the emphysema observed in COPD. In smokers who develop COPD there is an activation of adaptive immunity, with an infiltration of CD4+ and, especially, CD8 + cells. CD8 + cells are cytotoxic to epithelial cells through the release of granzymes and perforin, which can further induce apoptosis of alveolar cells. Moreover, any reduction in neutrophil apoptosis or dysregulation of macrophage uptake of apoptotic neutrophils could lead to chronic inflammation and tissue injury. Increased rates of T-cell apoptosis may lead to a defective immune response to infective organisms, contributing to the high frequency of infections seen in COPD. Increased apoptosis of skeletal muscle could be responsible for the skeletal muscle atrophy, the main cause of unexplained weight loss in patients with COPD. This paper is a review of the current knowledge on the apoptotic pathways involved in COPD pathogenesis and their interaction with other known contributing factors.

Figure 1

Lung epithelial cell apoptosis. Increased apoptosis of epithelial cells may account for the decreased vascular endothelial growth factor (VEGF) expression, resulting in alveolar endothelial cells death. The compromised microcirculation resulting from endothelial cell damage may further promote pneumocyte cell death. Increased elastolytic activity in apoptotic lung epithelial cells amplifies the destruction of alveolar elastin. The subsequent destruction of the basement membrane and the loss of cell–extracellular matrix attachments lead to further apoptosis of the surrounding cells. Abbreviations: BM, basement membrane; ECM, extracellular matrix.

Figure 2

Oxidative stress of cigarette smoke in “susceptible” smokers activates adaptive immunity, predisposing dendritic cells to clonal expansion of CD4 + and especially of cytotoxic CD8 + cells, inducing epithelial cell death by perforin.