Trauma-hemorrhage and hypoxia differentially influence kupffer cell phagocytic capacity: Role of hypoxia-inducible-factor-1α and phosphoinositide 3-kinase/akt activation

Academic Article


  • OBJECTIVE: We investigated whether Kupffer cell phagocytosis is differentially regulated following hypoxia (by breathing hypoxic gas) and trauma-hemorrhage. We hypothesized that the differences might result from a differential activation of hypoxia-inducible factor (HIF)-1α and phosphoinositide 3-kinase (PI3K)/Akt pathway under those conditions. BACKGROUND: HIF-1α is a biologic O2 sensor enabling adaptation to hypoxia. Studies have shown that under hypoxic conditions, HIF-1α enhances macrophage phagocytosis. Trauma-hemorrhage also produces a hypoxic insult with HIF-1α activation; however, macrophage phagocytosis is suppressed under those conditions. Thus, signaling molecules other than HIF-1α should be taken into consideration in the regulation of macrophage phagocytosis following cellular hypoxia or trauma-hemorrhage. METHODS:: Male C3H/HeN mice were subjected to sham operation, trauma-hemorrhage (laparotomy, 90 minutes hemorrhagic shock, MAP 35 ± 5 mm Hg followed by resuscitation) or hypoxia (5% O2 for 120 minutes). The trauma-hemorrhage and hypoxia groups received Wortmannin (PI3K inhibitor), YC-1 (HIF-1α inhibitor) or vehicle at the time of maximum bleedout in the trauma-hemorrhage group or at a PaO2 of 30 mm Hg during hypoxic air inhalation. Mice were killed 2 hours later and samples/cells collected. RESULTS:: While the systemic and Kupffer cell hypoxic states were similar in the trauma-hemorrhage and hypoxia groups, phagocytic capacity was suppressed following trauma-hemorrhage but enhanced in the hypoxia group. Kupffer cells from both groups showed increased HIF-1α activation, which was prevented by Wortmannin or YC-1 treatment. The increase in Kupffer cell phagocytosis following hypoxemia was also prevented by Wortmannin or YC-1 treatment. Akt activation was suppressed in the trauma-hemorrhage group, but enhanced in the hypoxia group. Wortmannin and YC-1 treatment prevented the increase in Akt activation. CONCLUSIONS:: These findings indicate that the suppression of Kupffer cell phagocytosis following trauma-hemorrhage is independent of cellular hypoxia and activation of HIF-1α, but it is possibly related to suppression of the Akt activation. © 2009 by Lippincott Williams & Wilkins.
  • Published In

  • Annals of Surgery  Journal
  • Digital Object Identifier (doi)

    Author List

  • Hsieh CH; Nickel EA; Hsu JT; Schwacha MG; Bland KI; Chaudry IH
  • Start Page

  • 995
  • End Page

  • 1001
  • Volume

  • 250
  • Issue

  • 6