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.