| HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. | |
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MedLine Citation:
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PMID: 20689059 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1α-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1α deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1β, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1β mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights. |
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Authors:
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Rena Feinman; Edwin A Deitch; Anthony C Watkins; Billy Abungu; Iriana Colorado; Kolenkode B Kannan; Sharvil U Sheth; Francis J Caputo; Qi Lu; Madhuri Ramanathan; Shirhan Attan; Chirag D Badami; Danielle Doucet; Dimitrios Barlos; Marta Bosch-Marce; Gregg L Semenza; Da-Zhong Xu |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-05 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 299 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-29 Completed Date: 2010-10-28 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
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Languages: eng Pagination: G833-43 Citation Subset: IM |
Affiliation:
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UMDNJ-New Jersey Medical School, Dept. of Surgery, Newark, 07103, USA. feinmarr@umdnj.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Cytokines / genetics, metabolism Gene Expression Regulation / physiology Genotype Hypoxia-Inducible Factor 1, alpha Subunit / genetics*, metabolism Inflammation / metabolism* Intestinal Diseases / metabolism*, pathology Intestinal Mucosa / metabolism, pathology Intestines / injuries*, metabolism, pathology Lung / metabolism, pathology Lung Injury / metabolism, pathology Mice Permeability RNA, Messenger / genetics, metabolism Reperfusion Injury / metabolism*, pathology Shock, Hemorrhagic / metabolism, pathology |
| Grant Support | |
ID/Acronym/Agency:
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1P50GM069790/GM/NIGMS NIH HHS; R01-HL55338/HL/NHLBI NIH HHS; T32-GM069330/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Messenger |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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