title: alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis.
abstract: 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.
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ipetrach@iupui.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Iwona
authors.initials: I
authors.lastname: Fijalkowska
authors.forename: Terry R
authors.initials: TR
authors.lastname: Medler
authors.forename: Jarrett
authors.initials: J
authors.lastname: Skirball
authors.forename: Pedro
authors.initials: P
authors.lastname: Cruz
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhen
authors.forename: Horia I
authors.initials: HI
authors.lastname: Petrache
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002474:Cell-Free System; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000201:enzymology*; D008171:Lung Diseases / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000515:alpha 1-Antitrypsin / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D061945:Caspase Inhibitors; D000515:alpha 1-Antitrypsin; D053148:Caspase 3