Ghrelin in Critical Illness

Yang

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

et al. 2017

Sepsis is a leading cause of mortality in intensive care units, and is more common in the geriatric population. The control of hyperinflammation has been suggested as a therapeutic approach in sepsis, but to date clinical trials utilizing this strategy have not lead to an effective treatment. In addition to hyperinflammation, patients with sepsis often experience a state of immunosuppression, which serves as an important determinant for increased morbidity and mortality. We previously used aged animals to demonstrate the effectiveness of combined treatment with human ghrelin (Ghr) and human growth hormone (GH) in improving organ injury and survival in septic animals. Here, we hypothesized that combined treatment with Ghr and GH could improve immune function in septic aged animals. Male 24-month-old rats were subjected to cecal ligation and puncture (CLP) for sepsis induction. Human Ghr (80 nmol/kg BW) plus GH (50 μg/kg BW) or vehicle (normal saline) was administrated subcutaneously at 5 h after CLP. The ex vivo production of TNF-α, IL-6 and IL-10 to LPS-stimulation, as well as TNF-α, IL-6, IL-10 and INF-γ production to anti-CD3/anti-CD28 antibody-stimulation, in splenocytes isolated 20 h after CLP, was significantly decreased compared to production of these cytokines in splenocytes from sham animals. The production of cytokines from splenocytes isolated from septic animals that received the combined treatment, however, was significantly higher than from those isolated from vehicle-treated septic animals. Combined treatment prevented the loss of splenic CD4+ and CD8+ T cells in septic aged rats, and reduced lymphocyte apoptosis. Combined treatment also inhibited an increase in the regulatory T cell (Treg) population and expression of the immune co-inhibitory molecule PD-1 in the spleens of septic aged rats. In contrast, expression of HLA-DR was increased after combined treatment with Ghr and GH. Based on these findings, we conclude that co-administration of Ghr and GH is a promising therapeutic tool for reversing immunosuppression caused by sepsis in the geriatric population.

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of human ghrelin and growth hormone: Attenuation of immunosuppression in septic aged rats

Yang

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

et al. 2017

“…Here, we demonstrated that ghrelin reduced TGF-β levels in the serum in septic aged animals and ameliorated sepsis-induced immune suppression. Human ghrelin has been administered into human subjects in clinical studies, showing excellent e cacy and safety pro le (52). Ghrelin has 93% homology in its amino acid sequence between human and rat or human and mouse (53).…”

Section: Discussionmentioning

confidence: 99%

Correction of immunosuppression in aged septic rats by human ghrelin and growth hormone through the vagus nerve-dependent inhibition of TGF-β production

Ochani

et al. 2020

Preprint

Abstract Background: Co-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. Methods: Male 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. Results: Serum 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 (HLA) expression, attenuated lymphopenia, and cleaved caspase-3 levels in splenocytes in 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. Conclusions: Ghrelin and GH attenuate immunosuppression in aged septic rats through the vagus nerve-dependent inhibition of TGF-β production.

“…Here, we demonstrated that ghrelin reduced TGF-β levels in the serum in septic aged animals and ameliorated sepsis-induced immune suppression. Human ghrelin has been administered into human subjects in clinical studies, showing excellent efficacy and safety profile (45). Ghrelin has 93% homology in its amino acid sequence between human and rat or human and mouse (46).…”

Section: Discussionmentioning

confidence: 99%

Correction of immunosuppression in aged septic rats by human ghrelin and growth hormone through the vagus nerve-dependent inhibition of TGF-β production

Ochani

et al. 2020

Preprint

Background: Co-administration of human ghrelin and growth hormone (GH) reverse immunesuppression in septic aged animals, but the mechanism remains elusive. Here we hypothesize that ghrelin and GH co-treatment restores immune response in aged septic rats by inhibiting the production of transforming growth factor-β (TGF-β), an immunoregulatory cytokine through the vagus nerve.Methods: Male 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.Results: Serum 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 in splenocytes of CLP rats 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 (HLA) expression, attenuated lymphopenia and cleaved caspase-3 levels in splenocytes in septic aged rats. Vagotomy diminished those beneficial effects of ghrelin and GH treatment to sepsis rats. In vitro addition of ghrelin or 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.Conclusions: Ghrelin and GH attenuates immunosuppression in aged septic rats through the vagus nerve-dependent inhibition of TGF-β production.