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-Melanocyte–stimulating Hormone Inhibits Lung Injury after Renal Ischemia/Reperfusion

Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Robert A. Star, M.D., Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 3N108, 10 Center Drive, Bethesda, MD 20892-1268. E-mail: Robert_Star{at}nih.gov

Combined acute renal and pulmonary failure has a very high mortality. In animals, lung injury develops after shock or visceral or renal ischemia. -Melanocyte–stimulating hormone (-MSH) is an antiinflammatory cytokine, which inhibits inflammatory, apoptotic, and cytotoxic pathways implicated in acute renal injury. We sought to determine if -MSH inhibits acute lung injury after renal ischemia and to determine the early mechanisms of -MSH action. Mice were subjected to renal ischemia treated with vehicle or -MSH. At early time points, we measured organ histology, leukocyte accumulation, myeloperoxidase activity, activation of nuclear factor-B, p38 mitogen-activated protein kinase, c-Jun, and activator protein-1 pathways, in addition to messenger RNA for intracellular adhesion molecule-1 and tumor necrosis factor-. Renal ischemia rapidly activated kidney and lung nuclear factor-B, p38 mitogen-activated protein kinase, c-Jun, and activator protein-1 pathways, and distant lung injury. -MSH administration immediately before reperfusion significantly decreased kidney and lung injury and prevented activation of kidney and lung transcription factors and stress response genes, and lung intracellular adhesion molecule-1 and tumor necrosis factor- at early time points after renal ischemia/reperfusion. We conclude that distant lung injury occurs rapidly after renal ischemia. -MSH protects against both kidney and lung damage after renal ischemia, in part, by inhibiting activation of transcription factors and stress genes early after renal injury.

Key Words: inflammation • nuclear factor-B • p38 • leukocytes • intracellular adhesion molecule-1 • tumor necrosis factor-

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