1. Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury
- Author
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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, and Francis J. Caputo
- Subjects
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 - Abstract
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.
- Published
- 2011