Abstract
Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE) and its variants in chronic obstructive pulmonary disease (COPD). In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/-) exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema.
Highlights
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and premature mortality in the United States and an epidemic worldwide
Upon long-term exposure to cigarette smoke, despite having enlarged airspaces at baseline, receptor for advanced glycation end products (RAGE)-/- mice did not develop significant airspace enlargement compared to wild type mice
Protection from smoke-induced emphysema in RAGE-/- mice was based upon morphometric analysis with less increase in airspace dimensions, respiratory mechanics with less loss of lung recoil, and less cellular damage and apoptosis
Summary
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and premature mortality in the United States and an epidemic worldwide. Cigarette smoke exposure is a major risk factor in the development of COPD [1]. Progression of emphysema is attributed to increased inflammation, with elevated attendant oxidative stress, and protease activity, leading to cellular apoptosis [3] and loss of elastin fibers. Despite advances in understanding the cellular and molecular mechanisms mediating the development of the disease, the precise molecular pathways and mediators leading to emphysema is not definitively known. Animal models of emphysema have been used to better understand the pathogenesis of COPD. Genetic engineering in mice has made it possible to manipulate gene expression to better understand its contribution to the pathobiology of the disease [4].
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