Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury
| Autor: | Rena Feinman, Billy Abungu, Iriana Colorado, Kolenkode B. Kannan, Edwin A. Deitch, Gregg L. Semenza, Anthony C. Watkins, Xiaofa Qin, Qi Lu, Diego Reino, David Palange, Da-Zhong Xu, Francis J. Caputo |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Pathology Genotype Physiology Acute Lung Injury Blotting Western Ischemia Nitric Oxide Synthase Type II Enzyme-Linked Immunosorbent Assay Inflammation Lung injury Permeability Mice Intestinal mucosa Mucosal Biology Malondialdehyde Physiology (medical) Internal medicine medicine Animals Intestinal Mucosa Peroxidase Mice Knockout Intestinal permeability Hepatology biology Caspase 3 Reverse Transcriptase Polymerase Chain Reaction Gastroenterology medicine.disease Intestines Mice Inbred C57BL Nitric oxide synthase Intestinal Diseases Endocrinology Reperfusion Injury biology.protein Hypoxia-Inducible Factor 1 medicine.symptom Multiple organ dysfunction syndrome Reperfusion injury |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 300:G853-G861 |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gut-origin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxia-inducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1α-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1α deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1β mRNA levels. Furthermore, partial HIF-1α deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1α+/− mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1α protein levels nor caused significant gut and lung injury in wild-type or HIF-1α+/− mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role. |
| Databáze: | OpenAIRE |
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