PERSISTENT HIF-1α ACTIVATION IN GUT ISCHEMIA/REPERFUSION INJURY: POTENTIAL ROLE OF BACTERIA AND LIPOPOLYSACCHARIDE


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Abstract

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-1α and constitutive HIF-1β 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-1α protein levels were induced in rats subjected to trauma (laparotomy) plus hemorrhagic shock for 90 min relative to their trauma sham-shock and naïve counterparts and that this trauma hemorrhagic shock-induced mucosal HIF-1α 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-1α 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-α 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-1α response would persist on reoxygenation if the enterocytes were cocultured with bacteria. P. aeruginosa, an enteric bacterium, markedly induced enterocyte HIF-1α protein levels under normoxic conditions. Furthermore, the addition of P. aeruginosa during either the hypoxic or reoxygenation phase prevented the degradation of HIF-1α protein levels. Moreover, the observation that lipopolysaccharide induced HIF-1α 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-1α activation is an early reperfusion-independent event in models of gut ischemia-reperfusion and that this HIF-1α response is potentiated by the presence of P. aeruginosa or lipopolysaccharide.

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