PROJECT 1: Alveolar cell apoptosis represents one of the major pathobiological processes that account for the loss of alveolar septae and tissue destruction in emphysema. Our overall concept underlying this SCCOR proposal is that the interaction of inflammation and apoptotic cell destruction due to disruption of lung cellular maintenance determines the magnitude of lung destruction in chronic obstructive pulmonary disease (COPD). Although the prevailing paradigm of emphysema development in patients with alpha-1 antitrypsin (A1AT) deficiency emphasizes the role of A1AT as an elastase inhibitor, serine protease inhibitors (Serpins), including A1 AT, have broader biological effects beyond their classical action as protease inhibitors. It is our goal to identify novel biological roles of A1 AT that might enhance our understanding of the pathogenesis of alveolar cell injury leading to emphysema. We hypothesize that A1 AT prevents emphysema by binding to and inhibitingactive caspase-3, leading to alveolar protection against apoptosis, a critical step of alveolar destruction in emphysema. This basic science project relies onan integrated approach involving the VEGF receptor blockade model of emphysema and adeno-associated virus transduction of human A1AT in vivo, and on focused mechanistic studies using cell cultures and cell- free systems to probe for the interaction of A1 AT and caspase-3.We have developed state of the art experimental assessment of emphysema lungs, based on standardized morphometry, lung imaging, pulmonary function tests (with the support of Molecular Pathophysiology Core D), and end points related to apoptosis, oxidative stress, and the proapoptotic lipid ceramide.
Our specific aims are (1) To demonstrate that A1AT prevents the development of emphysema in mice by blocking apoptosis, and thus reducing oxidative stress and ceramide levels. (2) To determine whether A1 AT protects pulmonary endothelial cells from apoptosis by a direct intracellular inhibition of caspase-3 activation; and (3) To identify whether in patients with emphysema, post-translational alterations in A1AT (oxidation, nitrosylation, or polymerization) impair the anti-apoptotic effect of A1 AT. Discovery of novel mechanisms of intracellular entry and activity of alpha-1 antritrypsin and may provide an opportunity improve our therapeutic approaches in alpha 1 antitrypsin deficiency- and smoking-induced emphysema. We will collaborate closely with Project 4 to determine whether cigarette smoke lung injury in the developing lung life impairs antiapoptotic functions of A1AT. We plan to translate our mechanistic insights of the novel antiapoptotic actions of A1AT in the investigation of posttranslational modifications of A1AT in patients with COPD (with Project 2) and exposure to environmental particulates (with Project 5) that may render A1 AT inactive against active caspase-3.
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