Effects of NF- B inhibition on mesenteric ischemia-reperfusion injury

Zou, Lei, Bashir Attuwaybi, and Bruce C. Kone. Effects of NKB inhibition on mesenteric ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 284: G713–G721, 2003. First published December 4, 2002; 10.1152/ ajpgi.00431.2002.—Mesenteric ischemia-reperfusion injury is a serious complication of shock. Because activation of nuclear factorB (NFB) has been implicated in this process, we treated rats with vehicle or the I Binhibitor BAY 11-7085 (25 mg/kg ip) 1 h before mesenteric ischemia-reperfusion (45 min of ischemia followed by reperfusion at 30 min or 6 h) and examined the ileal injury response. Vehicle-treated rats subjected to ischemia-reperfusion exhibited severe mucosal injury, increased myeloperoxidase (MPO) activity, increased expression of interleukin-6 and intercellular adhesion molecule 1 protein, and a biphasic peak of NFB DNA-binding activity during the 30-min and 6-h reperfusion courses. In contrast, BAY 11-7085-pretreated rats subjected to ischemiareperfusion exhibited less histological injury and less interleukin-6 and intercellular adhesion molecule 1 protein expression at 30 min of reperfusion but more histological injury at 6 h of reperfusion than vehicle-treated rats subjected to ischemia-reperfusion. Studies with phosphorylation site-specific antibodies demonstrated that I Bphosphorylation at Ser32,Ser36 was induced at 30 min of reperfusion, whereas tyrosine phosphorylation of I Bwas induced at 6 h of reperfusion. BAY 11-7085 inhibited the former, but not the latter, phosphorylation pathway, whereas -melanocytestimulating hormone, which is effective in limiting late ischemia-reperfusion injury to the intestine, inhibited tyrosine phosphorylation of I B. Thus NFB appears to play an important role in the generation and resolution of intestinal ischemia-reperfusion injury through different activation pathways.