The role of Z alpha-1 antitrypsin in the pathogenesis of emphysema. (360G-Wellcome-078854_Z_05_Z)

Alpha-1 antitrypsin (AT) is a major serine proteinase inhibitor whose main function is to protect the lung from proteolysis by neutrophil elastase. The Z variant (E342K) is prone to form polymers which accumulate as inclusions in the hepatocyte predisposing Z-AT homozygotes to cirrhosis. The low plasma levels of Z-AT predispose early onset panacinar emphysema. Polymeric AT may in part be responsible for the previously described exaggerated inflammatory response in Z-AT homozygotes. Polymers of Z-AT are present emphysematous lungs, and are chemotactic to neutrophils and preliminary data suggests that they also induce the secretion of interleukin-8 from type II alveolar cells. The factors that cause the formation of polymers within the lung are not known. In vitro, their formation is accelerated by increasing concentration and temperature. Furthermore, Based on the structural biology of polymerisation we have identified peptide inhibitors of polymerisation. The key scientific objectiv es of this work are to (1). elucidate the factors that cause polymerisation of Z-AT within the lung (2). assess whether polymeric AT causes Interleukin-8 secretion from type II pneumocytes (3). to assess whether potential therapeutic agents are efficacious in vivo.