Cell and Molecular Mediators involved in damage and repair in emphysema using mouse models

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and mortality in the United States and an epidemic worldwide. COPD pathologically manifests as emphysema, which is characterized by the abnormal and permanent airspace enlargement. Current research strives to understand the exact sequence of events triggering and leading to the progression of this disease, with the continued hope of finding a cure. The overarching aim of the current study was to investigate the role for the receptor for advanced glycation end products (RAGE) and a distal bronchial progenitor cell population (DBPCs) in mediating alveolar damage and repair using murine models of emphysema.\ud RAGE has gained importance in the context of COPD in the past decade. Highly expressed in normal adult lung tissue; its expression is altered in the context of lung injury. The present study tests the hypothesis that RAGE mediates cigarette smoke induced alveolar injury based on its previously described pro-inflammatory function. RAGE knockout mice (RAGE-/-) were used to investigate the contribution of this receptor towards the development of cigarette smoke induced emphysema. Our data indicates RAGE’s key contribution towards cigarette smoke induced emphysema, mediated through neutrophil recruitment and increased loss of tissue elastance.\ud Emphysema is thought to result from the disruption of a delicate balance that exists within the alveolar compartment; accentuated by failure at endogenous attempts to repair in the presence of extensive inflammation and loss of underlying basement membrane. Using a transgenic mouse line (CC10-Cre x Rosa26-LacZ) developed in our laboratory, we trace and confirm the migration of a distal bronchial progenitor cell population from the bronchoalveolar duct junction (BADJ)/ terminal bronchioles into the adjacent injured alveolar compartment. We further confirm our findings in a knock-in mouse line (CC10-iCre X Rosa26-LacZ) and thereby authenticate the contribution of these progenitor cells towards repopulating the injured alveolus. \ud This study shows that RAGE mediates early neutrophil recruitment leading to the pathogenic progression of alveolar damage and elucidates the contribution of a CC10 expressing bronchial progenitor arising from the distal airways leading to alveolar repopulation in the context of emphysema.\u