Rationale: Our recent study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and ghrelin administration improves organ blood flow via a nuclear factor-kappaB (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. Objective: 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). At 5h after CLP, a bolus intravenous injection of 2-nmol ghrelin was followed by a continuous infusion of 12-nmol ghrelin via a mini-pump for 15h. Samples were harvested 20h post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinfammatory 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 by radioactive microspheres. In additional animals, the necrotic cecum was excised 20h post-CLP and 10-day survival was recorded. Main Results: Pulmonary levels of ghrelin decreased significantly 20h post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, downregulated 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.