Delayed Administration of ??-Melanocyte-Stimulating Hormone or Combined Therapy with Bay 11-7085 Protects Against Gut Ischemia???Reperfusion Injury

Abstract

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.

Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers

“…These results further strengthen the role of αMSH as a potent antiinflammatory molecule [5,14] which exerts its effect by inhibition of the NF-κB transcription factor. Indeed, NF-κB inhibition was found to be central in the protective effect of α-MSH against oxidative stress in IEC-6 rat intestinal cells [40] and against ischemia/reperfusion induced intestinal injury in rats [19,20]. …”

“…In a rat model of chemically induced acute and chronic colitis α-MSH reduced pathological weight loss, fecal blood, TNF-α and nitric oxide production in colon tissue [17] and macroscopic colitis lesions [18]. Protective effect of α-MSH was also described in rat models of intestinal ischemia/reperfusion, where NF-κB induced inflammation has a central role in the pathomechanism [19,20]. …”

??-Melanocyte Stimulating Hormone Protects Against H2o2-Induced Inhibition of Wound Restitution in Iec-6 Cells via a Syk Kinase??? And Nf-???????Dependent Mechanism

“…These distinct phases coincided with NF-B activation through different IB␣ phosphorylation pathways-an early phase representing Ser-32, Ser-36 phosphorylation of IB␣ (11), which was inhibited by BAY 11-7085, and a later phase corresponding to tyrosine phosphorylation of IB␣, which was inhibited by the tridecapeptide ␣-melanocyte-stimulating hormone (␣-MSH) (8)(9)(10). In the aggregate, our data suggested that NF-B activation by the classical pathway of serine phosphorylation of IB␣ plays an important role in the injury response of the ileum during the early reperfusion period following mesenteric ischemia.…”

“…In previous work, we showed that mesenteric I/R results in a biphasic activation pattern of NF-B DNA-binding activity in the postischemic rat ileum during reperfusion (8)(9)(10). These distinct phases coincided with NF-B activation through different IB␣ phosphorylation pathways-an early phase representing Ser-32, Ser-36 phosphorylation of IB␣ (11), which was inhibited by BAY 11-7085, and a later phase corresponding to tyrosine phosphorylation of IB␣, which was inhibited by the tridecapeptide ␣-melanocyte-stimulating hormone (␣-MSH) (8)(9)(10).…”

Mesenteric Vascular Dysfunction After Cardiopulmonary Bypass With Cardiac Arrest Is Aggravated by Coexistent Heart Failure

“…The ischemia is consequent to the nonphysiologic perfusion during CPB, a potent stimulus for the release of endogenous splanchnic vasoconstrictors such as angiotensin II (4), and the activation of complement system (5) and proinflammatory cytokines (6,7), which also activate platelets and leukocytes (8,9) to form cellular aggregates capable of occluding vessels within the microcirculation. Free radical production and related cytotoxicity are pivotal as intermediates of these factors in various types of mesenteric ischemia and reperfusion injury (9,10).…”