Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury.
Publication/Presentation Date
5-1-2011
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.
Volume
300
Issue
5
First Page
853
Last Page
861
ISSN
1522-1547
Published In/Presented At
Kannan, K. B., Colorado, I., Reino, D., Palange, D., Lu, Q., Qin, X., Abungu, B., Watkins, A., Caputo, F. J., Xu, D. Z., Semenza, G. L., Deitch, E. A., & Feinman, R. (2011). Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury. American journal of physiology. Gastrointestinal and liver physiology, 300(5), G853–G861. https://doi.org/10.1152/ajpgi.00459.2010
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
21183660
Department(s)
Administration and Leadership
Document Type
Article