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HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury
- Source :
- American Journal of Physiology-Gastrointestinal and Liver Physiology. 299:G833-G843
- Publication Year :
- 2010
- Publisher :
- American Physiological Society, 2010.
-
Abstract
- 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.
- Subjects :
- Genotype
Physiology
Apoptosis
Inflammation
Shock, Hemorrhagic
Lung injury
Inflammation/Immunity/Mediators
Permeability
Mice
Intestinal mucosa
Physiology (medical)
medicine
Animals
RNA, Messenger
Intestinal Mucosa
Lung
Intestinal permeability
Hepatology
biology
business.industry
Gastroenterology
Lung Injury
Hypoxia (medical)
Hypoxia-Inducible Factor 1, alpha Subunit
medicine.disease
Intestines
Nitric oxide synthase
Intestinal Diseases
Gene Expression Regulation
Reperfusion Injury
Immunology
biology.protein
Cytokines
medicine.symptom
Multiple organ dysfunction syndrome
business
Reperfusion injury
Subjects
Details
- ISSN :
- 15221547 and 01931857
- Volume :
- 299
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Accession number :
- edsair.doi.dedup.....d90df5e3ccbc0653b91bc5ffbbc4cc65