GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia.
It has been reported that growth hormone (GH)-releasing peptide-2 (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 (ip) with LPS (1 mg/kg) and/or GHRP-2 (100 microg/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-alpha were evaluated as possible mediators of GHRP-2 actions. LPS increased serum levels of transaminases and nitrites/nitrates. Moreover, LPS increased hepatic TNF-alpha and decreased hepatic IGF-I mRNAs. GHRP-2 administration attenuated the effects of LPS on transaminases, nitrites/nitrates, TNF-alpha, 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-alpha mRNA both in vehicle rats and 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 an endotoxin-induced increase in transaminases and nitrite/nitrate release as well as in TNF-alpha 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 that seems to be mediated by IGF-I, TNF-alpha, and nitric oxide. Our data also suggest that the anti-inflammatory effect of GHRP-2 in the liver is exerted on nonparenchymal cells.
Granado
Miriam
M
Department of Physiology, Faculty of Medicine, Complutense Univ., Avda. Complutense s/n, 28040 Madrid, Spain.
Martín
Ana Isabel
AI
López-Menduiña
María
M
López-Calderón
Asunción
A
Villanúa
M Angeles
MA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D002478:Cells, Cultured; D018920:Coculture Techniques; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology; D006505:Hepatitis / Q000276:immunology / Q000517:prevention & control*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009842:Oligopeptides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; C091874:growth hormone-releasing peptide-2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase