PARTIAL HIF-1?? DEFICIENCY ATTENUATES ISCHEMIA REPERFUSION-MEDIATED GUT AND LUNG INJURY

In both humans and animal models, after ischemia/reperfusion (I/R) injury, the gut has been implicated as contributing to systemic inflammation and distant organ injury. Hypoxia inducible factor (HIF-1), composed of oxygen-labile HIF-1α and constitutive HIF-1β subunits, is a major regulator of the hypoxic/ischemic response. In both superior mesenteric artery occlusion (SMAO) and trauma hemorrhagic shock models, our earlier studies demonstrated that the in vivo intestinal mucosal response to gut I/R is associated with a prolonged increase in HIF-1α expression that is not rapidly lost upon reperfusion. To elucidate the functional significance of the intestinal HIF-1α response to gut I/R in vivo, partially deficient HIF-1α+/− and HIF- 1α+/+ mice were subjected to SMAO and Sham-SMAO for 45 min followed by 3 hr of reperfusion. The magnitude of SMAO-induced villous injury was approximately 4-fold greater in the wild-type than the partially HIF-1α deficient mice (p<0.05). Negligible villous injury was evident in both Sham-SMAO operated HIF-1α+/+ and HIF-1α+/− mice. Ileal HIF-1α protein levels were reduced in SMAO-induced HIF-1α+/− mice as compared to their SMAO-induced HIF-α+/+ counterparts. Similarly, the incidence of lung injury was approximately twofold higher in the wild-type mice as compared to the HIF-1α+/− (p<0.01). Our results suggest that partial HIF-1α deficiency significantly attenuates SMAO-induced gut and lung injury. Since HIF-1 regulates iNOS expression and iNOS has been implicated in gut-mediated I/R injury, we determined whether HIF-1-α induced gut injury is associated with an augmented iNOS response. Negligible ileal iNOS protein expression was detected in SMAO-induced HIF-1α+/− mice as compared to SMAO-induced HIF-1α+/+ mice. Our findings suggest that persistent elevation of HIF-1α after gut I/R is deleterious and contributes to the development of distant organ damage