Abstract
BackgroundCo-administration of human ghrelin and growth hormone (GH) reverse immunosuppression in septic aged animals, but the mechanism remains elusive. Here, we hypothesize that ghrelin and GH co-treatment restores the immune response in aged septic rats by inhibiting the production of transforming growth factor-β (TGF-β), an immunoregulatory cytokine, through the vagus nerve.MethodsMale aged Fischer rats (22–23-month-old) were made septic by cecal ligation and puncture (CLP) with or without dissecting the vagus nerve (vagotomy). Human ghrelin and GH or vehicle (PBS) were administrated subcutaneously at 5 h post CLP. After 20 h of CLP, serum and spleens were harvested.ResultsSerum TGF-β levels were increased in septic aged rats, while ghrelin and GH treatment significantly reduced its levels. Expression of TGF-β in the spleen was upregulated after sepsis, while ghrelin and GH treatment significantly inhibited its expression. TNF-α and IL-6 levels were significantly reduced after ex vivo LPS stimulation of splenocytes from rats that underwent CLP compared to sham rats; while these levels were significantly higher in splenocytes from ghrelin and GH-treated CLP rats compared to vehicle-treated CLP rats. Ghrelin and GH treatment reduced program death receptor-1 (PD-1) expression, increased human leukocyte antigen-DR (HLA-DR) expression, attenuated lymphopenia, and cleaved caspase-3 levels in the spleen of septic aged rats. Vagotomy diminished the beneficial effects of ghrelin and GH treatment in septic rats. In vitro, the addition of ghrelin, GH, or ghrelin and GH together had no effect on restoring immune response in splenocytes from CLP rats following LPS stimulation, indicating the requirement of the vagus nerve for ghrelin and GH’s effect.ConclusionsGhrelin and GH attenuate immunosuppression in aged septic rats through the vagus nerve-dependent inhibition of TGF-β production.
Highlights
Sepsis is a life-threatening condition that arises due to a dysregulated immune response to infection leading to excessive inflammation and organ injury (Singer et al 2016)
Even though we recently demonstrated that the combined treatment with ghrelin and growth hormone (GH) (GG) were able to reverse immunosuppression in aged septic rats, the underlying mechanism involving the potential role of transforming growth factor-β (TGF-β) in GG-mediated restoration of immune response had not been studied (Zhou et al 2017)
Combined treatment with ghrelin and GH reduces TGF-β production in aged septic rats through the vagus nerve We found that the protein levels of TGF-β1 in the serum and spleen were increased by 2.1 and 2.0 folds, respectively in aged rats at 20 h after cecal ligation and puncture (CLP) as compared to the sham-operated animals (Fig. 1a, b)
Summary
Sepsis is a life-threatening condition that arises due to a dysregulated immune response to infection leading to excessive inflammation and organ injury (Singer et al 2016). Studies with human septic patients demonstrate that immunosuppression is the predominant cause of morbidity and mortality in sepsis (Hotchkiss et al 2013; Boomer et al 2011). Persistent inflammation, T cell exhaustion, and lymphocytopenia are observed in elderly patients after sepsis (Inoue et al 2014). Those patients are susceptible to secondary infection with lower survival rates compared to young septic patients (Inoue et al 2014). Studies have shown that severe sepsis and septic shock are mainly observed in elderly patients (> 65 years of age), giving rise to significantly higher mortality rate of about 80% (Boomer et al 2011; Martin et al 2006; Opal et al 2005; Hepper et al 2013). We hypothesize that ghrelin and GH co-treatment restores the immune response in aged septic rats by inhibiting the production of transforming growth factor-β (TGF-β), an immunoregulatory cytokine, through the vagus nerve
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