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)-kappa 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-kappa B plays any role in it. Objectives: To test the hypothesis that ghrelin reduces severe sepsis-induced ALI and mortality through inhibition of NF-kappa B. Methods: Sepsis was induced in rats by cecal ligation and puncture (CLIP). Five hours after CLIP, 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-kappa B p65 and I kappa B alpha expression and NF-kappa 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-CLIP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-kappa 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-kappa B.
