Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Ann Surg. 2009 Dec;250(6):995-1001. doi: 10.1097/SLA.0b013e3181b0ebf8.
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.
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.
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.
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.
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.
我们研究了在缺氧（通过呼吸低氧气体）和创伤-出血后，枯否细胞吞噬作用是否存在差异调节。我们假设，这些情况下的差异可能是由于缺氧诱导因子（HIF）-1α和磷脂酰肌醇 3-激酶（PI3K）/Akt 通路的差异激活所致。
HIF-1α是一种生物 O2 传感器，使细胞能够适应缺氧。研究表明，在缺氧条件下，HIF-1α增强巨噬细胞吞噬作用。创伤-出血也会产生缺氧损伤并激活 HIF-1α；然而，在这些情况下，巨噬细胞吞噬作用受到抑制。因此，在细胞缺氧或创伤-出血后调节巨噬细胞吞噬作用时，除了 HIF-1α 之外，还应考虑其他信号分子。
雄性 C3H/HeN 小鼠接受假手术、创伤-出血（剖腹术，90 分钟出血性休克，MAP35+/-5mmHg 后复苏）或缺氧（5%O2 120 分钟）。在创伤-出血组最大出血时或在缺氧空气吸入时 PaO2 为 30mmHg 时，创伤-出血组和缺氧组给予 Wortmannin（PI3K 抑制剂）、YC-1（HIF-1α 抑制剂）或载体。2 小时后处死小鼠并收集样本/细胞。
虽然创伤-出血组和缺氧组的全身和枯否细胞缺氧状态相似，但创伤-出血后吞噬能力受到抑制，而在缺氧组中增强。两组枯否细胞的 HIF-1α 激活均增加，Wortmannin 或 YC-1 治疗可预防。缺氧后枯否细胞吞噬作用的增加也被 Wortmannin 或 YC-1 治疗所预防。创伤-出血组 Akt 激活受到抑制，而缺氧组增强。Wortmannin 和 YC-1 治疗可预防 Akt 激活的增加。
这些发现表明，创伤-出血后枯否细胞吞噬作用的抑制与细胞缺氧和 HIF-1α 的激活无关，但可能与 Akt 激活的抑制有关。
