Effects of NF-kappa B inhibition on mesenteric ischemia-reperfusion injury.
Mesenteric ischemia-reperfusion injury is a serious complication of shock. Because activation of nuclear factor-kappaB (NF-kappaB) has been implicated in this process, we treated rats with vehicle or the IkappaB-alpha inhibitor 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 NF-kappaB DNA-binding activity during the 30-min and 6-h reperfusion courses. In contrast, BAY 11-7085-pretreated rats subjected to ischemia-reperfusion 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 IkappaB-alpha phosphorylation at Ser(32),Ser(36) was induced at 30 min of reperfusion, whereas tyrosine phosphorylation of IkappaB-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 ischemia-reperfusion injury to the intestine, inhibited tyrosine phosphorylation of IkappaB-alpha. Thus NF-kappaB appears to play an important role in the generation and resolution of intestinal ischemia-reperfusion injury through different activation pathways.
Zou
Lei
L
Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Attuwaybi
Bashir
B
Kone
Bruce C
BC
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D007082:Ileum / Q000098:blood supply / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D013152:Splanchnic Circulation / Q000502:physiology*; D013450:Sulfones; D000521:alpha-MSH / Q000494:pharmacology
D000890:Anti-Infective Agents; C416282:BAY 11-7085; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D009570:Nitriles; D013450:Sulfones; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D000521:alpha-MSH; D009195:Peroxidase