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

Am J Pathol. 2006 Oct;169(4):1155-66. doi: 10.2353/ajpath.2006.060058.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Capillaries / cytology
  • Capillaries / drug effects
  • Capillaries / enzymology
  • Caspase 3 / metabolism*
  • Caspase Inhibitors*
  • Cell-Free System
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology
  • Humans
  • Lung / blood supply
  • Lung / cytology
  • Lung / enzymology*
  • Lung Diseases / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • alpha 1-Antitrypsin / metabolism*
  • alpha 1-Antitrypsin / pharmacology*


  • Caspase Inhibitors
  • alpha 1-Antitrypsin
  • Caspase 3