Human Ghrelin Ameliorates Organ Injury and Improves Survival after Radiation Injury Combined with Severe Sepsis

Abstract

In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. The purpose of this study is to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI) and, if so, the potential mechanism responsible for the benefit. To study this, adult male rats were exposed to 5-Gy whole body irradiation followed by cecal ligation and puncture (CLP, a model of sepsis) 48 h thereafter. Human ghrelin (30 nmol/rat) or vehicle (saline) was infused intravenously via an osmotic minipump immediately after radiation exposure. Blood and tissue samples were collected at 20 h after RCI (68 h after irradiation or 20 h after CLP) for various measurements. To determine the longterm effect of human ghrelin after RCI, the gangrenous cecum was removed at 5 h after CLP and 10-d survival was recorded. In addition, vagotomy or sham vagotomy was performed in sham and RCI animals immediately prior to ghrelin administration, and various measurements were performed at 20 h after RCI. Our results showed that serum levels of ghrelin and its gene expression in the stomach were decreased markedly at 20 h after RCI. Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to rebalancing the dysregulated sympathetic/parasympathetic nervous systems.

The Anti-Inflammatory and Neuroprotective Effects of Ghrelin in Subarachnoid Hemorrhage-Induced Oxidative Brain Damage in Rats

“…On the other hand, the current findings demonstrate that ghrelin treatment depressed MPO activity and ROS generation, and helped to repair the BBB, suggesting that the protective effects of ghrelin in SAH-induced brain injury is mediated in part by blocking tissue neutrophil infiltration and the associated ROS-induced damage. In accordance with the present data, it was previously shown that ghrelin ameliorates organ injury in several inflammation models by inhibiting proinflammatory cytokine production and myeloperoxidase activity (Brzozowski et al, 2006;Iseri et al, 2008;Kasımay et al, 2006;Sehirli et al, 2008;Shah et al, 2009;Wu et al, 2008). Furthermore, ghrelin has been shown to exhibit anti-inflammatory functions against T cells and macrophages by inhibiting mononuclear cell binding and nuclear factor-kB activation (Chorny et al, 2008;Dixit et al, 2004;Li et al, 2004;Wassem et al, 2008).…”

Development of A Novel Murine Model of Combined Radiation and Peripheral Tissue Trauma Injuries

“…Combined injuries promotes bacterial translocation and, therefore, ileus seen in our model, at least partially, supports the hypothesis that gut damage drives lung injury. Indeed, suppression of inflammation in the gut by administration of ghrelin in the model of combined radiation and sepsis injury suppressed neutrophil infiltration in lungs, also supporting our hypothesis (12). …”

“…In preclinical studies radiation has been combined with a number of different injuries (1, 4) including burns (9–11), sepsis (12), incisional wounds (13) and hemorrhage (14). These studies show the increased lethality in combined injuries, more severe tissue damage and the importance of timing of the wounding for survival.…”

Human ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve

“…The mechanism of ghrelin’s protection towards inflammatory responses in various pathological conditions has been unraveling over the past few years. In this regard, we have previously shown that subdiaphragmatic vagotomy in rats prevents the anti-inflammatory effects of ghrelin in sepsis, radiation combined injury and gut I/R injury 28,29,57 . In the present study, we showed that ghrelin’s protective effect in renal I/R injury is indeed mediated by the vagus nerve.…”