HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury

Abstract

mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 299: G833-G843, 2010. First published August 5, 2010 doi:10.1152/ajpgi.00065.2010.-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-1␣-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-1␣ deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1␣ deficiency reduced TNF-␣, IL-1␤, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1␤ 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. hemorrhagic shock; inflammation; multiple organ dysfunction syndrome; acute lung injury IN PATIENTS SUSTAINING major trauma, the development of the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction (MODS) is a major clinical problem resulting in 50 -80% of all deaths in surgical intensive care units. Since the pathophysiology of this syndrome remains incompletely understood and therapy remains largely supportive (16), studies focusing on the basic biology of traumainduced SIRS, organ injury/dysfunction, and MODS have been major areas of investigation. These mechanistic studies have generated several working hypotheses, one of which is the gut hypothesis of MODS. A key element in the gut hypothesis of MODS is that a splanchnic ischemia-reperfusion (I/R) insult leading to gut inflammation and loss of barrier function is the initial triggering event that turns the gut into the "motor" of MODS (19). However, the exact mechanisms by which gut I/R leads to intestinal injury and how an intestinal ischemic insult is transduced into a systemic inflammatory response remains incomplete. To date, the majority of the molecular and cellular studies investigating shock-induced gut injury and gut-induced MODS have focused pr...

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

“…Fourth, these studies also demonstrate that resistance to intestinal I/R injury is associated with resistance to lung injury and inflammation in partially HIF-1␣-deficient mice. The direct relationship between HIF-1 activation and SMAO-induced intestinal I/R injury validates our recent study demonstrating that HIF-1 activation-mediated gut and lung injury in a global trauma-hemorrhagic shock model (15).…”

Induced Hypothermia Preserves the Functional Enterocyte Mass in A Porcine Multiple Trauma Model

“…grade 0 = normal mucosa, grade 1 = development of subepithelial space at the apex of the villous with or without capillary congestion, grade 2 = extension of subepithelial space with moderate lifting of subepithelial layer from the lamina propria, grade 3 = massive epithelial lifting down the side of the villi and a few tips possibly denuded, grade 4 = denuded villi with lamina propria and dilated capillaries exposed, and grade 5 = digestion and disintegration of lamina propria, haemorrhage, and ulceration (25,26).…”

Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats

“…A scoring system to grade the degree of lung injury was employed [18] . Simultaneously, gut injury was assessed according to the grading systems for villous injury as described previously [12] . The grading was performed by a blinded pathologist.…”

“…Myeloperoxidase (MPO) activity was determined as an index of neutrophil accumulation in the lungs. As described previously [12] , the MPO activity in the supernatants was determined by measuring the H 2 O 2 -mediated oxidation of o-dianisidine hydrochloride at 460 nm and normalizing relative to the num- …”

“…In LPS-induced ALI, HIF-1α expression exacerbates acute lung epithelial cell injury and the expression of the BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3) gene and many proinflammatory cytokines [11] . Moreover, it has been shown that partial HIF-1α deficiency (HIF-1α +/-) could alleviate lung injury induced by T/HS or superior mesenteric artery occlusion (SMAO) in mice [12,13] . In this study, we hypothesized that lung HIF-1α activation could be potentially maladaptive or injurious and could contribute to lung injury induced by T/HS.…”