Open AccessDelayed Administration of ??-Melanocyte-Stimulating Hormone or Combined Therapy with Bay 11-7085 Protects Against Gut Ischemia???Reperfusion Injury
Author(s) -
Lei Zou,
Norio Sato,
Bashir Attuwaybi,
Bruce C. Kone
Publication year - 2003
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/01.shk.0000091205.08003.fd
Subject(s) - myeloperoxidase , reperfusion injury , ischemia , medicine , pharmacology , superior mesenteric artery , endocrinology , alpha (finance) , heme oxygenase , tyrosine phosphorylation , heme , inflammation , chemistry , receptor , biochemistry , enzyme , surgery , construct validity , patient satisfaction
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.