| Epithelial cell death is an important contributor to oxidant-mediated acute lung injury. | |
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MedLine Citation:
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PMID: 20959557 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown. OBJECTIVES: To determine whether oxidant-mediated activation of the intrinsic or extrinsic apoptotic pathway contributes to the development of acute lung injury. METHODS: Exposure of tissue-specific or global knockout mice or cells lacking critical components of the apoptotic pathway to hyperoxia, a well-established mouse model of oxidant-induced lung injury, for measurement of cell death, lung injury, and survival. MEASUREMENTS AND MAIN RESULTS: We found that the overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice exposed to hyperoxia. The conditional loss of BAX and BAK in the lung epithelium prevented hyperoxia-induced cell death in alveolar epithelial cells, ameliorated hyperoxia-induced lung injury, and prolonged survival in mice. By contrast, Cyclophilin D-deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury. Mice globally deficient in the BH3-only proteins BIM, BID, PUMA, or NOXA, which are proximal upstream regulators of BAX and BAK, were not protected against hyperoxia-induced lung injury suggesting redundancy of these proteins in the activation of BAX or BAK. CONCLUSIONS: Mitochondrial oxidant generation initiates BAX- or BAK-dependent alveolar epithelial cell death, which contributes to hyperoxia-induced lung injury. |
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Authors:
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G R Scott Budinger; Gökhan M Mutlu; Daniela Urich; Saul Soberanes; Leonard J Buccellato; Keenan Hawkins; Sergio E Chiarella; Kathryn A Radigan; James Eisenbart; Hemant Agrawal; Sara Berkelhamer; Siegfried Hekimi; Jianke Zhang; Harris Perlman; Paul T Schumacker; Manu Jain; Navdeep S Chandel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-10-19 |
Journal Detail:
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Title: American journal of respiratory and critical care medicine Volume: 183 ISSN: 1535-4970 ISO Abbreviation: Am. J. Respir. Crit. Care Med. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-18 Completed Date: 2011-06-22 Revised Date: 2012-04-16 |
Medline Journal Info:
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Nlm Unique ID: 9421642 Medline TA: Am J Respir Crit Care Med Country: United States |
Other Details:
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Languages: eng Pagination: 1043-54 Citation Subset: AIM; IM |
Affiliation:
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Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, IL 60611, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acute Lung Injury
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etiology* Animals Apoptosis / physiology Cyclophilins / physiology Disease Models, Animal Hyperoxia / complications, physiopathology Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria / metabolism Oxidative Stress / physiology Pulmonary Alveoli / chemistry, cytology, physiopathology Rats Rats, Sprague-Dawley Reactive Oxygen Species / analysis Respiratory Mucosa / metabolism, physiopathology* Superoxide Dismutase / metabolism bcl-2 Homologous Antagonist-Killer Protein / metabolism bcl-2-Associated X Protein / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AI067590/AI/NIAID NIH HHS; AR050250/AR/NIAMS NIH HHS; AR054796/AR/NIAMS NIH HHS; ES013995/ES/NIEHS NIH HHS; ES015024/ES/NIEHS NIH HHS; HL071643/HL/NHLBI NIH HHS; HL071643-07/HL/NHLBI NIH HHS; R01 AR050250-07/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Bak1 protein, mouse; 0/Bax protein, mouse; 0/Reactive Oxygen Species; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; EC 1.15.1.1/Superoxide Dismutase; EC 1.15.1.1/superoxide dismutase 2; EC 5.2.1.-/Cyclophilins; EC 5.2.1.8/cyclophilin D |
| Comments/Corrections | |
Comment In:
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Am J Respir Crit Care Med. 2011 Apr 15;183(8):964-5
[PMID:
21498818
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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