Combined Administration of Human Ghrelin and Human Growth Hormone Attenuates Organ Injury and Improves Survival in Aged Septic Rats

Abstract

Sepsis is a major healthcare concern, especially in the elderly population. The use of an animal model closely resembling clinical conditions in this population may provide a better prediction in translating bench studies to the bedside. Ghrelin inhibits sympathetic nerve activity and inflammation in young septic animals; however, aged animals become hyporesponsive to ghrelin. In this study, we evaluated the efficacy of combined human ghrelin and growth hormone (GH) for sepsis treatment in the elderly utilizing a clinically relevant animal model of sepsis. Male Fischer 344 rats 22 to 24 months old were subjected to cecal ligation and puncture (CLP). Human ghrelin plus GH or vehicle (normal saline) was administered subcutaneously at 5 h after CLP. At 20 h after CLP, blood and tissue samples were collected for various analyses. Combined treatment attenuated serum levels of lactate, lactate dehydrogenase, creatinine, blood urea nitrogen, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in aged septic rats. The integrity of the microscopic structure in the lungs, liver and kidneys was well preserved after treatment. Expression of IL-6, TNF-α, macrophage inflammatory protein-2 and keratinocyte-derived chemokine as well as myeloperoxidase activity and caspase-3 activation were significantly reduced in the lungs and liver of treated rats. Moreover, treated rats showed an improvement in cardiovascular function and increased expression of ghrelin receptor and c-fos in the brainstem. Finally, the 10-d survival of aged septic rats was increased from 29% to 64% after combined treatment and was associated with less body weight loss. Our findings warrant the development of combined human ghrelin and GH for sepsis treatment in the geriatric population.

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

“…Likewise, immune cells in septic patients have also been reported to suffer from anergy and therefore fail to proliferate or secrete cytokines in response to their specific antigens [3, 39]. Furthermore, defective T cell proliferation and cytokine secretion were shown to be correlated with higher mortality in septic patients [40], which corresponds to our previous survival study in septic aged rats [22]. …”

“…Using the clinically-relevant CLP model of polymicrobial sepsis [33]. we have previously reported that combined treatment with human Ghr and GH improves 10-day survival in septic aged rats from 29% to 64% [22]. In this study, we further demonstrated that combined treatment with human Ghr and GH restores the responsiveness of isolated splenocytes to LPS- and anti-CD3/anti-CD28 antibody-stimulation; prevents the loss of splenic CD4 + and CD8 + T cells by apoptosis; reduces the splenic T reg population; inhibits the expression of splenic PD-1; and increases the expression of splenic HLA-DR in septic aged rats.…”

“…Human GH has been approved by the Food and Drug Administration for the treatment of short stature due to GH deficiency in the pediatric population, chronic renal insufficiency, short bowel syndrome in adults, and AIDS-associated cachexia. Although administration of high-dose GH has been associated with increased mortality in patients with prolonged critical illness [61], a very low-dose GH was used in our combined treatment as a Ghr-sensitizing agent, with beneficial effects demonstrated in septic aged animals [19, 22]. …”

“…Sepsis in aged rats was induced by cecal ligation and puncture (CLP) as described previously [22]. Briefly, anesthesia was induced by isoflurane inhalation.…”

“…Previous studies found that the combination of Ghr with low-dose growth hormone (GH) significantly increased Ghr receptor expression, markedly enhancing responsiveness to Ghr in aged septic animals. Co-administration of ghrelin and growth hormone reduced organ injury and increased survival in aged septic animals [22]. Since the integrity of immune function plays a crucial role in sepsis-related mortality, especially in the geriatric population, in the current study we further investigate the effect of combined Ghr and GH treatment in modulating immune activity in septic aged animals.…”