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Ghrelin Protects against Experimental Sepsis by Inhibiting High-Mobility Group Box 1 Release and by Killing Bacteria^1,2

Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Cientificas, Granada, Spain

Sepsis, a life-threatening complication of infections and the most common cause of death in intensive care units, is characterized by a hyperactive and out-of-balance network of endogenous proinflammatory cytokines. None of the current therapies are entirely effective, illustrating the need for novel therapeutic approaches. Ghrelin (GHR) is an orexigenic peptide that has emerged as a potential endogenous anti-inflammatory factor. In this study, we show that the delayed administration of GHR protects against the mortality in various models of established endotoxemia and sepsis. The therapeutic effect of GHR is mainly mediated by decreasing the secretion of the high mobility box 1 (HMGB1), a DNA-binding factor that acts as a late inflammatory factor critical for sepsis progression. Macrophages seem to be the major cell targets in the inhibition of HMGB1 secretion, in which GHR blocked its cytoplasmic translocation. Interestingly, we also report that GHR shows a potent antibacterial activity in septic mice and in vitro. Remarkably, GHR also reduces the severity of experimental arthritis and the release of HMGB1 to serum. Therefore, by regulating crucial processes of sepsis, such as the production of early and late inflammatory mediators by macrophages and the microbial load, GHR represents a feasible therapeutic agent for this disease and other inflammatory disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Fondo de Investigaciones Sanitarias and Junta de Andalucia (Grupos de Excelencia) and Fondo de Investigaciones Sanitarias Ph.D. fellowship (to A.C.).

² A.C. and M.D. designed research, performed research, and wrote the paper. E.G.-R. and P.A. performed research.

³ Address correspondence and reprint requests to Dr. Mario Delgado, Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, Avenida Conocimiento, PT Ciencias de la Salud, Granada 18100, Spain. E-mail address: mdelgado{at}ipb.csic.es

⁴ Abbreviations used in this paper: HMGB1, high mobility group box 1; GHR, ghrelin; CLP, cecal ligation and puncture; CIA, collagen-induced arthritis; DiBAC₄(3), bis-(1,3-dibutylbarbituric acid) trimethine oxonol; FAM-GHR, carboxyfluorescein-labeled GHR.