{alpha}-1 Antitrypsin Inhibits Caspase-3 Activity, Preventing Lung Endothelial Cell Apoptosis

• Published in: The American journal of pathology Vol. 169; no. 4; pp. 1155 - 1166
• Main Authors: Petrache, Irina, Fijalkowska, Iwona, Medler, Terry R, Skirball, Jarrett, Cruz, Pedro, Zhen, Lijie, Petrache, Horia I, Flotte, Terence R, Tuder, Rubin M
• Format: Journal Article
• Language: English
• Published: ASIP 01-10-2006
• Subjects: Adeno-associated virus
• DOI: 10.2353/ajpath.2006.060058
• EISSN: 1525-2191
• ISSN: 0002-9440

a-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.