It has been reported that GHRP-2, a ghrelin receptor agonist, has an anti-inflammatory effect. We investigated whether this GH secretagogue attenuates liver injury in LPS treated rats. Wistar rats were simultaneously injected i.p. with LPS (1 mg/kg) and/or GHRP-2 (100 µg/kg). Serum levels of aspartate and alanine transaminases were measured as an index of liver damage. Circulating nitrites/nitrates and hepatic IGF-I and TNF- were evaluated as possible mediators of GHRP-2 actions. LPS increased serum levels of transaminases and nitrites/nitrates. Moreover, LPS increased hepatic TNF- and decreased hepatic IGF-I mRNAs. GHRP-2 administration attenuated the effects of LPS on transaminases, nitrites/nitrates, TNF- and IGF-I in vivo. This GHRP-2 effect does not seem to be due to modifications in food intake, since fasting did not modify serum levels of transaminases, serum nitrites/nitrates and hepatic TNF- mRNA both in vehicle or in LPS-injected rats. To elucidate whether GHRP-2 is acting directly on the liver, cocultures of hepatocytes and nonparenchymal cells and monocultures of isolated hepatocytes were incubated with LPS and GHRP-2. The ghrelin receptor agonist prevented endotoxin-induced increase in transaminases and nitrite/nitrate release as well as in TNF- mRNA and increased IGF-I mRNA from cocultures of hepatocytes and nonparenchymal cells, but not from monocultures. In summary, these data indicate that GHRP-2 has a protective effect on the liver in LPS-injected rats, which seems to be mediated by IGF-I, TNF- and NO. Our data also suggest that the anti-inflammatory effect of GHRP-2 in the liver is exerted on nonparenchymal cells.