Abstract
Widespread use of ionizing radiation has led to the realization of the danger associated with radiation exposure. Although studies in radiation countermeasures were initiated a half century ago, an effective therapy for a radiomitigator has not been identified. Ghrelin is a gastrointestinal hormone, and administration of ghrelin is protective in animal models of injuries including radiation combined injury. To test whether ghrelin can be protective in whole body irradiaton (WBI) alone, male Sprague Dawley (SD) rats were treated with human ghrelin (20 nmol/rat) daily for 6 days starting at either 24 h or 48 h after 10 Gray (Gy) WBI and survival outcome was examined. The 10 Gy WBI produced a LD70/30 model in SD rats (30% survival in 30 days). The survival rate in rats treated with ghrelin starting at 24 h was significantly improved to 63% and when treatment was initiated at 48 h, the survival remained at 61%. At 7 days post WBI, plasma ghrelin was significantly reduced from the control value. Ghrelin treatment starting at 24 h after WBI daily for 6 days improved histological appearance of the intestine, reduced gut permeability, serum endotoxin levels and bacterial translocation to the liver by 38%, 42% and 61%, respectively at day 7 post WBI. Serum glucose and albumin were restored to near control levels with treatment. Ghrelin treatment also attenuated WBI-induced intestinal apoptosis by 62% as evidenced by TUNEL staining. The expression of anti-apoptotic cell regulator Bcl-xl was decreased by 38% in the vehicle and restored to 75% of the control with ghrelin treatment. Increased expression of intestinal CD73 and pAkt were observed with ghrelin treatment, indicating protection of the intestinal epithelium after WBI. These results indicate that human ghrelin attenuates intestinal injury and mortality after WBI. Thus, human ghrelin can be developed as a novel mitigator for radiation injury.
Highlights
The widespread use of nuclear energy in generation of electrical power, and in diagnostic and treatment modalities, has led to greater recognition of the serious and dangerous effects of PLOS ONE | DOI:10.1371/journal.pone.0118213 February 11, 2015Human Ghrelin Protects against whole body irradiation (WBI) in Rats
To evaluate ghrelin’s effect on WBI, 10 Gy WBI rats were treated with a vehicle or human ghrelin (20 nmol/rat) once a day for 6 days starting at either 24 h or 48 h after WBI
When WBI rats were treated with human ghrelin starting at 24 h after WBI, the survival rate was 63% which was significantly higher than that of the vehicle group (Fig. 1A)
Summary
The widespread use of nuclear energy in generation of electrical power, and in diagnostic and treatment modalities, has led to greater recognition of the serious and dangerous effects of PLOS ONE | DOI:10.1371/journal.pone.0118213 February 11, 2015. Acute radiation syndrome (ARS) is defined as signs and symptoms relating to exposure to radiation. Efforts aimed at radiation countermeasures were initiated more than half a century ago, there still exists an unmet medical need for an effective therapy in radiation sickness or ARS. The biological effects of ghrelin are mediated through the growth hormone secretagogue receptor type 1a (GHSR1a, ghrelin receptor), a 7 transmembrane domain Gq protein-coupled receptor. Stimulation of pituitary GHSR1a by ghrelin is reported to induce growth hormone release [6,7,8]. A large body of evidence has indicated other physiological functions of ghrelin which are mediated by both central and peripheral ghrelin receptors [9]. Ghrelin has been linked to the regulation of feeding, energy homeostasis, and function in the pituitary, gastrointestinal, cardiovascular, and immune system. We sought to determine whether ghrelin could be protective against whole body irradiation (WBI) and be developed as a radiomitigator for the victims of ARS
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