title: Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia 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.
authors.affiliation: Dept. of Surgery, UMDNJ-New Jersey Medical School, Newark, 07103, USA.
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Iriana
authors.initials: I
authors.lastname: Colorado
authors.forename: Diego
authors.initials: D
authors.lastname: Reino
authors.forename: David
authors.initials: D
authors.lastname: Palange
authors.forename: Qi
authors.initials: Q
authors.lastname: Lu
authors.forename: Xiaofa
authors.initials: X
authors.lastname: Qin
authors.forename: Billy
authors.initials: B
authors.lastname: Abungu
authors.forename: Anthony
authors.initials: A
authors.lastname: Watkins
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Caputo
authors.forename: Da-Zhong
authors.initials: DZ
authors.lastname: Xu
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Rena
authors.initials: R
authors.lastname: Feinman
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000502:physiology*; D007410:Intestinal Diseases / Q000473:pathology*; D007413:Intestinal Mucosa / Q000502:physiology; D007422:Intestines / Q000098:blood supply; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051793:Hypoxia-Inducible Factor 1; D008315:Malondialdehyde; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3