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Ghrelin Attenuates Sepsis-induced Acute Lung Injury and Mortality in Rats

¹ Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York

Correspondence and requests for reprints should be addressed to Ping Wang, M.D., The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail: pwang{at}nshs.edu

Rationale: Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-B–dependent pathway. However, it remains unknown whether ghrelin has any protective effects on severe sepsis–induced acute lung injury (ALI) and, if so, whether inhibition of NF-B plays any role in it.

Objectives: To test the hypothesis that ghrelin reduces severe sepsis–induced ALI and mortality through inhibition of NF-B.

Methods: Sepsis was induced in rats by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by continuous infusion of 12 nmol of ghrelin via a minipump for 15 hours. Samples were harvested 20 hours post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinflammatory cytokines were measured by ELISA. NF-B p65 and IB expression and NF-B activity were measured by Western blot analysis and ELISA, respectively. Pulmonary blood flow was measured with radioactive microspheres. In additional animals, the necrotic cecum was excised 20 hours post-CLP and 10-day survival was recorded.

Measurements and Main Results: Pulmonary levels of ghrelin decreased significantly 20 hours post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-B activation, and improved survival in sepsis. Administration of a specific ghrelin receptor antagonist worsened the survival rate after CLP and cecal excision.

Conclusions: Ghrelin can be developed as a novel treatment for severe sepsis–induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-B.

Key Words: peptide • cytokine • nuclear factor-B

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Levels of ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, are reduced in sepsis. However, there is only limited information on the protective effects of ghrelin in sepsis. What This Study Adds to the Field Ghrelin has a beneficial effect on sepsis-induced lung injury via a mechanism that involves inhibition of the nuclear factor-B pathway in the lungs.

 

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