Persistent HIF-1α activation in gut ischemia/reperfusion injury:: Potential role of bacteria and lipopolysaccharide
Persistent HIF-1α activation in gut ischemia/reperfusion injury:: Potential role of bacteria and lipopolysaccharide
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DOI：
10.1097/01.shk.0000135256.67441.3f
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发表时间：
2004-09-01
期刊：
影响因子：
3.1
通讯作者：
Feinman, R
中科院分区：
文献类型：
--
作者：
Koury, J;Deitch, EA;Feinman, R
在失血性休克的动物模型和临床环境中，休克引起的肠道缺血与全身性炎症反应综合征和远端器官损伤的发展有关，但转导这些事件的因素仍有待完全确定。由于缺氧诱导因子（HIF-1）是一种由氧不稳定的HIF-1 α和组成型HIF-1 β亚基组成的转录因子，调节缺氧和缺血的生理/病理生理反应，我们研究了HIF-1在两种大鼠肠道缺血再灌注模型中的反应。我们发现创伤（开腹）加失血性休克90分钟后大鼠的回肠核hif -1 α蛋白水平相对于创伤假休克和未受创伤的对照组有所改变，并且这种创伤失血性休克诱导的粘膜hif -1 α蛋白反应在再灌注1小时和3小时后持续存在。同样，在离体肠缺血再灌注损伤模型中，肠系膜上动脉闭塞45分钟，相对于假手术，核hif -1 α在肠粘膜中被诱导，并在再灌注后1小时和3小时持续存在。与体内反应类似，体外缺氧诱导三种不同肠细胞系（大鼠IEC-6和人Caco-2和HT-29细胞系）的hif - α表达。然而，与体内反应相反，HIF-1的表达在随后的再氧化中迅速消失。由于体内肠细胞暴露于细菌，我们测试了如果肠细胞与细菌共培养，体外hif -1 α反应是否会在再氧化时持续存在。P. aeruginosa是一种肠道细菌，在常温条件下显著诱导肠细胞hif -1 α蛋白水平。此外，在缺氧或再氧化阶段添加铜绿假单胞菌可以阻止hif -1 α蛋白水平的降解。此外，脂多糖在IEC-6细胞中诱导HIF-1 α表达的时间依赖性表明，暴露于铜绿假单胞菌对HIF-1的诱导不依赖于细菌的生存能力。总之，这些结果表明，在肠缺血-再灌注模型中，hif -1 α激活是一个早期的不依赖于再灌注的事件，并且这种hif -1 α反应会因铜绿假单胞菌或脂多糖的存在而增强。
In both animal models of hemorrhagic shock and clinical settings, shock-induced gut ischemia has been implicated in the development of the systemic inflammatory response syndrome and distant organ injury, yet the factors transducing these events remain to be fully determined. Because hypoxia-inducible factor (HIF-1), a transcription factor composed of oxygen-labile HIF-1alpha and constitutive HIF-1beta subunits, regulates the physiologic/pathophysiologic response to hypoxia and ischemia, we examined the HIF-1 response in two rat models of gut ischemia-reperfusion. We found that ileal nuclear HIF-1alpha protein levels were induced in rats subjected to trauma (laparotomy) plus hemorrhagic shock for 90 min relative to their trauma sham-shock and naive counterparts and that this trauma hemorrhagic shock-induced mucosal HIF-1alpha protein response persisted after 1 h and 3 h of reperfusion. Likewise, in a model of isolated gut ischemia-reperfusion injury, where the superior mesenteric artery was occluded for 45 min, nuclear HIF-1alpha were induced in the gut mucosa relative to their sham counterparts and persisted after 1 h and 3 h or reperfusion. Similar to the in vivo response, in vitro hypoxia induced HIF-alpha expression in three different enterocyte cell lines (rat IEC-6 and human Caco-2 and HT-29 cell lines). However, in contrast to the in vivo response, HIF-1 expression rapidly disappeared on subsequent reoxygenation. Because in vivo enterocytes are exposed to bacteria, we tested whether the in vitro HIF-1alpha response would persist on reoxygenation if the enterocytes were cocultured with bacteria. P. aeruginosa, an enteric bacterium, markedly induced enterocyte HIF-1alpha protein levels under normoxic conditions. Furthermore, the addition of P. aeruginosa during either the hypoxic or reoxygenation phase prevented the degradation of HIF-1alpha protein levels. Moreover, the observation that lipopolysaccharide induced HIF-1alpha expression in a time-dependent manner in IEC-6 cells indicated that the induction of HIF-1 by exposure to P. aeruginosa is not dependent on bacterial viability. In conclusion, these results suggest that HIF-1alpha activation is an early reperfusion-independent event in models of gut ischemia-reperfusion and that this HIF-1alpha response is potentiated by the presence of P. aeruginosa or lipopolysaccharide.