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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.

Apoptosis of alveolar macrophages (AMs) plays a pathogenic role in acute lung injury (ALI) and its severe type, acute respiratory distress syndrome (ARDS). Mesenchymal stem cells (MSCs) are promising therapeutic cells for preventing apoptosis and eliminating cellular injury. We investigated the effects of rat bone marrow mesenchymal stem cells (BMSCs) on lipopolysaccharide (LPS)-induced apoptosis in AMs using transwell experiments, and examined the underlying mechanisms LPS induced AMs apoptosis in a dose- and time-dependent fashion, whereas BMSCs reduced AMs apoptosis when co-cultured at appropriate ratios. BMSCs decreased expression of cleaved caspase-3 and the pro-apoptotic protein, Bax, whilst increased levels of the anti-apoptotic protein, Bcl-2, prolonging the lifespan of AMs in vitro. Promotion of AMs survival by BMSCs required down-regulation of p-GSK-3β and β-catenin in AMs. The anti-apoptosis action of BMSCs was reversed by SB216763, a specific inhibitor of GSK-3β that also activates Wnt/β-catenin signaling. In conclusion, BMSCs can attenuate AM apoptosis partially by suppressing the Wnt/β-catenin pathway.

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Ghrelin has proven to be protective against sepsis-induced acute lung injury (ALI) via anti-inflammatory effects. However, its mechanisms remain poorly understood. Alveolar macrophages (AMs) play a key role in mediating inflammatory responses during sepsis-induced ALI by secretion of cytokines and chemokines. This study was undertaken to investigate whether ghrelin suppresses inflammatory effects of AMs and therefore may help to attenuate sepsis-induced ALI. A sepsis model in rats was achieved using cecal ligation and puncture. Ghrelin treatment markedly improved histopathological changes in the lungs and reduced pulmonary inflammation in septic rats. NF-κB translocation and p-Akt and inducible nitric oxide synthase (iNOS) activities in AMs from septic rats were suppressed by ghrelin. In vitro data indicated that ghrelin decreased the levels of LPS-induced IL-1β, TNF-α, and IL-6, NF-κB translocation, and iNOS and Akt activities of AMs. Furthermore, the NF-κB/iNOS pathway or Akt signaling was positively correlated with LPS-induced inflammatory production of AMs in vitro. In conclusion, ghrelin exerts a protective role against sepsis-induced ALI probably by reducing the production of inflammatory cytokines from AMs via inhibition of the NF-κB/iNOS pathway or Akt signaling.

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Background The Oxford Acute Severity of Illness Score (OASIS) has shown fair prognosis predictive value in critically ill patients, but its predictive value has not been assessed in septic patients. Objective The aim of this study was to evaluate the performance of the OASIS for the assessment of mortality in septic patients, especially when compared with the Sepsis-related Organ Failure Assessment (SOFA) score. Methods A retrospective cohort study was conducted using data from a public database and septic patients were identified using the Sepsis-3 criteria. The primary outcome was hospital mortality. Data were mainly analyzed using multivariable logistic regression and receiver operating characteristic (ROC) curves. Sensitive analyses were performed in patients with an ICD-9-CM code for sepsis and ROC curves analyses were also conducted in septic patients stratified by the Simplified Acute Physiology Score (SAPS) II as subgroup analyses. Results A total of 10,305 septic patients were included. The OASIS was found to be significantly associated with hospital mortality (odds ratio 1.07 per one-point increase, 95% confidence interval [1.06–1.08]), while ROC curves analyses showed the discriminatory power of the OASIS for hospital mortality was statistically significantly lower than that of the SOFA score (area under the ROC curve: 0.652 vs 0.682, p < 0.001). Results of sensitive analyses were consistent, but the significant difference existed only when the SAPS II was higher than 50 according to results of the subgroup analyses. Conclusions The OASIS might serve as an initial predictor of clinical outcomes for septic patients, but one should be circumspect when it is applied to severer patients.

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