Intraischemic hypothermia differentially modulates oxidative stress proteins during mesenteric ischemia/reperfusion.

BACKGROUND

Thoracoabdominal aortic aneurysm repair requires obligatory mesenteric ischemia/reperfusion (I/R), eliciting an inflammatory response resulting in gut dysfunction and remote organ injury. Therapeutic hypothermia has been advocated for organ protection (ie, brain, spinal cord, and kidneys) during extensive aortic operation, and it has also been shown to differentially modulate proinflammatory gene transcription in the central nervous system. In other I/R models, nuclear factor Kappa-B (NF-(kappa)B) and inducible nitric oxide synthase (iNOS) worsen while heme oxygenase-1 (HO-1) protects against injury. We examined the effects of regional intraischemic hypothermia on mesenteric I/R-induced mucosal injury, NF-kappaB activation, and expression of iNOS and HO-1.

METHODS

Sprague-Dawley rats underwent sham laparotomy or superior mesenteric artery occlusion for 45 minutes with or without topical hypothermia (15 degrees -20 degrees C). Intestinal epithelial permeability to (14)C inulin was assessed at 6 hours of reperfusion. In a separate set of experiments, biopsies of the ileum were obtained at 6 hours of reperfusion for: 1) mucosal histologic injury assessed by a blinded observer; 2) NF-kappaB activation by electrophoretic mobility shift assay; and 3) iNOS and HO-1 protein expression by immunoblot.

RESULTS

Mesenteric I/R significantly increased intestinal permeability to (14)C inulin, histologic injury, activation of NF-kappaB, and iNOS and HO-1 expression when compared with sham control rats. In contrast, rats treated with intraischemic topical hypothermia exhibited intestinal permeability comparable with sham control rats, and reduced histologic injury. In addition, hypothermia prevented the activation of NF-kappaB and iNOS expression, but had no effect on HO-1 expression.

CONCLUSIONS

On the basis of these observations, we conclude that therapeutically applied intraischemic hypothermia protects the gut during mesenteric I/R. In addition, hypothermia prevented NF-kappaB activation while differentially modulating expression of the oxidative stress proteins iNOS and HO-1 in response to mesenteric I/R.