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(American Journal of Pathology. 2006;169:1155-1166.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060058

-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 and Rubin M. Tuder^*

From the Department of Medicine,^* Division of Pulmonary and Critical Care Medicine, and the Department of Pathology, Division of Cardiopulmonary Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Pediatrics, School of Medicine, University of Florida at Gainesville, Gainesville, Florida; and the Laboratory of Structural Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

-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.

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