| alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. | |
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MedLine Citation:
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PMID: 17003475 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Irina Petrache; Iwona Fijalkowska; Terry R Medler; Jarrett Skirball; Pedro Cruz; Lijie Zhen; Horia I Petrache; Terence R Flotte; Rubin M Tuder |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The American journal of pathology Volume: 169 ISSN: 0002-9440 ISO Abbreviation: Am. J. Pathol. Publication Date: 2006 Oct |
Date Detail:
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Created Date: 2006-09-27 Completed Date: 2006-11-24 Revised Date: 2010-09-16 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 1155-66 Citation Subset: AIM; IM |
Affiliation:
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Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ipetrach@iupui.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Capillaries / cytology, drug effects, enzymology Caspase 3 / antagonists & inhibitors*, metabolism* Cell-Free System Endothelial Cells / drug effects, enzymology Humans Lung / blood supply, cytology, enzymology* Lung Diseases / enzymology Male Mice Mice, Inbred C57BL alpha 1-Antitrypsin / metabolism*, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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K08 HL04396-04/HL/NHLBI NIH HHS; P01-DK58327/DK/NIDDK NIH HHS; R01-HL69877/HL/NHLBI NIH HHS; R01HL66554/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/alpha 1-Antitrypsin; EC 3.4.22.-/Caspase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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