α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis

Irina Petrache, Iwona Fijalkowska, Terry R. Medler, Jarrett Skirball, Pedro Cruz, Lijie Zhen, Horia I. Petrache, Terence R. Flotte, Rubin M. Tuder

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

α-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.

Original languageEnglish (US)
Pages (from-to)1155-1166
Number of pages12
JournalAmerican Journal of Pathology
Volume169
Issue number4
DOIs
StatePublished - Oct 2006
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Petrache, I., Fijalkowska, I., Medler, T. R., Skirball, J., Cruz, P., Zhen, L., Petrache, H. I., Flotte, T. R., & Tuder, R. M. (2006). α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. American Journal of Pathology, 169(4), 1155-1166. https://doi.org/10.2353/ajpath.2006.060058