Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine

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• 作者：Junru Wang ; Marjan Boerma ; Ashwini Kulkarni ; Morley D. Hollenberg ; Martin Hauer-Jensen
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2010
• 出版时间：15 July 2010
• 年：2010
• 卷：77
• 期：4
• 页码：1206-1212
• 全文大小：426 K

文摘

Purpose

Protease-activated receptor-2 (PAR₂) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR₂ is strikingly upregulated and exhibits increased activation in response to intestinal irradiation. We examined the mechanistic significance of radiation enteropathy development by assessing the effect of exogenous PAR₂ activation.

Methods and Materials

Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR₂ agonist (2-furoyl-LIGRLO-NH₂) or vehicle was injected intraperitoneally daily for 3 days before irradiation (before), for 7 days after irradiation (after), or both 3 days before and 7 days after irradiation (before-after). Early and delayed radiation enteropathy was assessed at 2 and 26 weeks after irradiation using quantitative histologic examination, morphometry, and immunohistochemical analysis.

Results

The PAR₂ agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR₂ agonist was associated with more severe mucosal injury and increased intestinal wall thickness in all three treatment groups (p <.05) compared with the vehicle-treated controls. The PAR₂ agonist also exacerbated the radiation injury score, serosal thickening, and mucosal inflammation (p <.05) in the before and before-after groups. The short-term exogenous activation of PAR₂ did not affect radiation-induced intestinal injury at 26 weeks.

Conclusion

The results of the present study support a role for PAR₂ activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR₂ antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.