α-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis

• DOI: 10.2353/ajpath.2006.060058
• Publication Date: 2006-12-13T19:54:42Z
• Authors: Irina Petrache; Iwona Fijalkowska; Terry R. Medler; Jarrett Skirball; Pedro Cruz; Lijie Zhen; Horia I. Petrache; Terence R. Flotte; Rubin M. Tuder
• Keywords: Lung Diseases; Male; 0301 basic medicine; Cell-Free System; Caspase 3; Endothelial Cells; Apoptosis; Caspase Inhibitors; Capillaries; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; alpha 1-Antitrypsin; Animals; Humans; Lung

alpha-1 Antitrypsin (A1AT) is an abundant circulating serpin with a postulated function in the lung of potently inhibiting neutrophil-derived proteases. Emphysema attributable to A1AT deficiency led to the concept that a protease/anti-protease imbalance mediates cigarette smoke-induced emphysema. We hypothesized that A1AT has other pathobiological relevant functions in addition to elastase inhibition. We demonstrate a direct prosurvival effect of A1AT through inhibition of lung alveolar endothelial cell apoptosis. Primary pulmonary endothelial cells internalized human A1AT, which co-localized with and inhibited staurosporine-induced caspase-3 activation. In cell-free studies, native A1AT, but not conformers lacking an intact reactive center loop, inhibited the interaction of recombinant active caspase-3 with its specific substrate. Furthermore, overexpression of human A1AT via replication-deficient adeno-associated virus markedly attenuated alveolar wall destruction and oxidative stress caused by caspase-3 instillation in a mouse model of apoptosis-dependent emphysema. Our findings suggest that direct inhibition of active caspase-3 by A1AT may represent a novel anti-apoptotic mechanism relevant to disease processes characterized by excessive structural cell apoptosis, oxidative stress, and inflammation, such as pulmonary emphysema.