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Am J Physiol Gastrointest Liver Physiol (December 4, 2002). doi:10.1152/ajpgi.00431.2002
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Articles in PresS, published online ahead of print December 4, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00431.2002
Submitted on October 10, 2002
Accepted on December 2, 2002

Effects of NF-{kappa}B Inhibition on Mesenteric Ischemia-reperfusion Injury

Lei Zou1, Bashir Attuwaybi2, and Bruce C. Kone1*

1 Department of Internal Medicine and of Integrative Biology and Pharmacology, The University of Texas Medical School at Houston, Houston, TX, USA; Trauma Research Center, The University of Texas Medical School at Houston, Houston, TX, USA
2 Department of Surgery, The University of Texas Medical School at Houston, Houston, TX, USA; Trauma Research Center, The University of Texas Medical School at Houston, Houston, TX, USA

* To whom correspondence should be addressed. E-mail: Bruce.C.Kone{at}uth.tmc.edu.

Mesenteric ischemia-reperfusion (I/R) injury is a serious complication of shock. Because activation of NF-{kappa}B has been implicated in this process, we treated rats with vehicle or the I{kappa}B-{alpha} inhibitor BAY 11-7085 (25 mg/kg I.P.) one hour before mesenteric I/R (45 min of ischemia; 30 min or 6 h reperfusion) and examined the ileal injury response. Vehicle-treated I/R rats exhibited severe mucosal injury, increased myeloperoxidase (MPO) activity, increased expression of IL-6 and ICAM-1 protein, and a biphasic peak of NF-{kappa}B DNA binding activity during the 30 min and 6 h reperfusion course. In contrast, BAY 11-7085-pretreated I/R rats exhibited less histologic injury and less IL-6 and ICAM-1 protein expression at 30 min of reperfusion, but worse histologic injury at 6 h of reperfusion compared to vehicle-treated I/R rats. Studies with phosphorylation site-specific antibodies demonstrated that I{kappa}B-{alpha} phosphorylation at Ser-32, Ser-36 was induced at 30 min of reperfusion, whereas tyrosine phosphorylation of I{kappa}B-{alpha} was induced at 6 h of reperfusion. BAY 11-7085 inhibited the former, but not the latter phosphorylation pathway, whereas {alpha}-melanocyte stimulating hormone, which is effective in limiting late I/R injury to the intestine, inhibited tyrosine phosphorylation of I{kappa}B-{alpha}. Thus, NF-{kappa}B appears to play an important role in both the generation and the resolution of intestinal I/R injury through different activation pathways.




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