Trauma-hemorrhage and hypoxia differentially influence kupffer cell phagocytic capacity: role of hypoxia-inducible-factor-1alpha and phosphoinositide 3-kinase/Akt activation.

Abstract

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)-1alpha and phosphoinositide 3-kinase (PI3K)/Akt pathway under those conditions.

BACKGROUND:

HIF-1alpha is a biologic O2 sensor enabling adaptation to hypoxia. Studies have shown that under hypoxic conditions, HIF-1alpha enhances macrophage phagocytosis. Trauma-hemorrhage also produces a hypoxic insult with HIF-1alpha activation; however, macrophage phagocytosis is suppressed under those conditions. Thus, signaling molecules other than HIF-1alpha 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-1alpha 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-1alpha 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-1alpha, but it is possibly related to suppression of the Akt activation.

• Authors: Chi-Hsun Hsieh, Eike A Nickel, Jun-Te Hsu, Martin G Schwacha, Kirby I Bland, Irshad H Chaudry
• Journal: Annals of surgery (Ann Surg) Vol. 250 Issue 6 Pg. 995-1001 (Dec 2009) ISSN: 1528-1140 [Electronic] United States
• PMID: 19855262 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Phosphatidylinositol 3-Kinases

Topics

• Abdominal Injuries (complications, metabolism, pathology)
• Animals
• Disease Models, Animal
• Enzyme Activation
• Enzyme-Linked Immunosorbent Assay
• Hemorrhage (complications, metabolism, pathology)
• Hypoxia (etiology, metabolism, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Kupffer Cells (metabolism, pathology)
• Liver (injuries, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C3H
• Phagocytosis (physiology)
• Phosphatidylinositol 3-Kinases (metabolism)