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

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Abstract
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)-κB–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-κB plays any role in it. Objectives: To test the hypothesis that ghrelin reduces severe sepsis–induced ALI and mortality through inhibition of NF-κB. 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-κB p65 and IκBα expression and NF-κB 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-κB 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-κB.