title: Ghrelin protects alveolar macrophages against lipopolysaccharide-induced apoptosis through growth hormone secretagogue receptor 1a-dependent c-Jun N-terminal kinase and Wnt/β-catenin signaling and suppresses lung inflammation.
abstract: Alveolar macrophages (AMs) undergo increased apoptosis during sepsis-induced acute respiratory distress syndrome (ARDS). Ghrelin exhibits an antiapoptotic effect in several cell types and protects against sepsis-induced ARDS in rats; however, the molecular mechanisms underlying this antiapoptotic effect remain poorly understood. In this study, we first examined the antiapoptotic effect of ghrelin on lipopolysaccharide (LPS)-stimulated AMs in vitro. In AMs, GH secretagogue receptor-1a (GHSR-1a), the ghrelin receptor, was expressed, and treatment of AMs with ghrelin markedly reduced LPS-induced apoptosis, mitochondrial transmembrane potential decrease, and cytochrome c release. These effects of ghrelin were mediated by GHSR-1a because a GHSR-1a-targeting small interfering RNA abolished the antiapoptotic action of ghrelin. LPS treatment activated the c-Jun N-terminal kinase (JNK) signaling pathway but inhibited the Wnt/β-catenin pathway. Interestingly, combined LPS-ghrelin treatment reduced JNK activation and increased Wnt/β-catenin activation. Furthermore, like ghrelin treatment, the addition of the JNK inhibitor SP600125 or the glycogen synthase kinase-3β inhibitor SB216763 rescued AMs from apoptosis. We also demonstrated that ghrelin altered the balance of Bcl-2-family proteins and inhibited caspase-3 activity. Next, we investigated whether ghrelin protected against septic ARDS in vivo. Sepsis was induced in male rats by performing cecal ligation and puncture; administration of ghrelin reduced sepsis-induced AMs apoptosis, pulmonary injury, protein concentrations in the bronchoalveolar lavage fluid, the lung neutrophil infiltration, and wet to dry weight ratio. However, administration of a specific ghrelin-receptor antagonist, [D-Lys-3]-GH-releasing peptide-6, abolished the beneficial effects of ghrelin. Collectively our results suggest that ghrelin exerts an antiapoptotic effect on AMs at least partly by inhibiting JNK and activating the Wnt/β-catenin pathway and thereby helps alleviate septic ARDS in rats.
authors.affiliation: Department of Medical Intensive Care Unit (B.L., M.Z., W.H., X.H., L.L.) and Research Center of Translational Medicine (D.Y.B.D.), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; and Department of Anatomy (H.Z.), Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Mian
authors.initials: M
authors.lastname: Zeng
authors.forename: Wanmei
authors.initials: W
authors.lastname: He
authors.forename: Xubin
authors.initials: X
authors.lastname: Huang
authors.forename: Liang
authors.initials: L
authors.lastname: Luo
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zhang
authors.forename: David Y B
authors.initials: DY
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D054439:Ghrelin / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008171:Lung Diseases / Q000188:drug therapy; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D054439:Ghrelin; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D054440:Receptors, Ghrelin; D051153:Wnt Proteins; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; D009195:Peroxidase; D048031:JNK Mitogen-Activated Protein Kinases