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 re-balancing the dysregulated sympathetic/parasympathetic nervous systems.
Highlights
There is a growing concern in the world about the exposure of radiation due to the threat of nuclear terrorism
The purpose of this study was to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI, radiation exposure followed by cecal ligation and puncture (CLP)) and, if so, the potential mechanism responsible for its benefit
Similar to CLP alone animals [19], serum levels of ghrelin in RCI animals decreased to 87 ± 20 pg/mL (P < 0.05), representing a 35% reduction at 20 h after RCI (68 h after irradiation or 20 h after CLP)
Summary
There is a growing concern in the world about the exposure of radiation due to the threat of nuclear terrorism. In the terrorist radiation exposure scenario, the amount of radiation may not be enough to cause immediate illness or large scale casualties, but radiation victims likely will suffer from injuries, infection, and sepsis secondary to the bomb blast. Infection and sepsis remain a critical problem with significant morbidity and mortality even in the modern era of criti-. Severe sepsis is the second leading cause of death among patients in non-coronary intensive care units (ICU) and the tenth leading cause of death overall in this nation [6,7,8,9]. It is expected that both the morbidity and mortality of sepsis increase after radiation exposure. Little information is available regarding radiation exposure followed by infection and sepsis
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