Delayed administration of alpha-melanocyte-stimulating hormone or combined therapy with BAY 11-7085 protects against gut ischemia-reperfusion injury.
Gut ischemia-reperfusion (I/R) injury is a serious complication of shock. Previously we demonstrated that the administration of alpha-melanocyte-stimulating hormone (MSH) immediately before mesenteric I/R protected against postischemic gut injury. In this report, we tested the therapeutic efficacy of alpha-MSH on gut I/R (60 min ischemia, 6 h reperfusion) injury when given at different time points of reperfusion. Rats underwent sham surgery or were treated with saline or with alpha-MSH that was given 1, 2, or 4 h after superior mesenteric artery clamping. Vehicle-treated I/R rats exhibited severe mucosal injury and increased NF-kappaB DNA binding activity, myeloperoxidase (MPO) activity, and interleukin-6 and heme oxygenase-1 (HO-1) expression. In contrast, rats given alpha-MSH at 1 h of reperfusion, but not 2 h or 4 h, exhibited much less mucosal injury. Rats given alpha-MSH at 1 h or 2 h of reperfusion, but not 4 h, exhibited less MPO activity, NF-kappaB DNA binding activity, and interleukin-6 protein and even higher levels of heme oxygenase-1 than vehicle-treated rats. In addition, we found that combined use of alpha-MSH, a known inhibitor of IkappaBalpha tyrosine phosphorylation, with BAY 11-7085, an inhibitor of IkappaBalpha Ser 32,36 phosphorylation, abrogates gut MPO induction and tissue injury at early and late time points of reperfusion. Thus, alpha-MSH, an endogenous peptide with a favorable side-effect profile, is effective in treating experimental gut I/R injury when given early after the initial ischemia and may represent a candidate therapy for gut I/R in humans in whom recognition and treatment are often delayed.
Zou
Lei
L
Department of Internal Medicine, Trauma Research Center, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Sato
Norio
N
Attuwaybi
Bashir O
BO
Kone
Bruce C
BC
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D004359:Drug Therapy, Combination; D024202:Electrophoretic Mobility Shift Assay; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles; D009195:Peroxidase / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013450:Sulfones; D000521:alpha-MSH / Q000494:pharmacology / Q000627:therapeutic use*
D000890:Anti-Infective Agents; C416282:BAY 11-7085; D015850:Interleukin-6; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D000521:alpha-MSH; D004247:DNA; D009195:Peroxidase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1