title: HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.
abstract: 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-1α-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-1α deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1β, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1β 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.
authors.affiliation: UMDNJ-New Jersey Medical School, Dept. of Surgery, Newark, 07103, USA. feinmarr@umdnj.edu
authors.forename: Rena
authors.initials: R
authors.lastname: Feinman
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Watkins
authors.forename: Billy
authors.initials: B
authors.lastname: Abungu
authors.forename: Iriana
authors.initials: I
authors.lastname: Colorado
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Sharvil U
authors.initials: SU
authors.lastname: Sheth
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Caputo
authors.forename: Qi
authors.initials: Q
authors.lastname: Lu
authors.forename: Madhuri
authors.initials: M
authors.lastname: Ramanathan
authors.forename: Shirhan
authors.initials: S
authors.lastname: Attan
authors.forename: Chirag D
authors.initials: CD
authors.lastname: Badami
authors.forename: Danielle
authors.initials: D
authors.lastname: Doucet
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Barlos
authors.forename: Marta
authors.initials: M
authors.lastname: Bosch-Marce
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Da-Zhong
authors.initials: DZ
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007410:Intestinal Diseases / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000293:injuries* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010539:Permeability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger