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

174 Citations (Scopus)

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

Fingerprint

Caspase 3
Emphysema
Endothelial Cells
Apoptosis
Lung
Peptide Hydrolases
Oxidative Stress
Serpins
Alveolar Epithelial Cells
Pulmonary Emphysema
Dependovirus
Staurosporine
Pancreatic Elastase
Smoke
Tobacco Products
Neutrophils
Inflammation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Petrache, I., Fijalkowska, I., Medler, T. R., Skirball, J., Cruz, P., Zhen, L., ... 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

α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. / Petrache, Irina; Fijalkowska, Iwona; Medler, Terry R.; Skirball, Jarrett; Cruz, Pedro; Zhen, Lijie; Petrache, Horia I.; Flotte, Terence R.; Tuder, Rubin M.

In: American Journal of Pathology, Vol. 169, No. 4, 10.2006, p. 1155-1166.

Research output: Contribution to journalArticle

Petrache, I, Fijalkowska, I, Medler, TR, Skirball, J, Cruz, P, Zhen, L, Petrache, HI, Flotte, TR & Tuder, RM 2006, 'α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis', American Journal of Pathology, vol. 169, no. 4, pp. 1155-1166. https://doi.org/10.2353/ajpath.2006.060058
Petrache, Irina ; Fijalkowska, Iwona ; Medler, Terry R. ; Skirball, Jarrett ; Cruz, Pedro ; Zhen, Lijie ; Petrache, Horia I. ; Flotte, Terence R. ; Tuder, Rubin M. / α-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. In: American Journal of Pathology. 2006 ; Vol. 169, No. 4. pp. 1155-1166.
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