Protease-activated receptor-2 (PAR2) is highly expressed throughout the gut and regulates 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 in 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 2 and 26 weeks after irradiation by quantitative histology, morphometry, and immuno-histochemical analysis.
The PAR2 agonist did not elicit changes in unirradiated (shielded) intestine. In contrast, in irradiated intestine procured 2 weeks after irradiation, administration of PAR2 agonist was associated with more sever mucosal injury and increased intestinal wall thickness in all 3 treatment groups (p < 0.05) compared to vehicle-treated controls. The PAR2 agonist also exacerbated radiation injury score, serosal thickening, and mucosal inflammation (p < 0.05) in the before and the before-after groups. Short term exogenous activation of PAR2 did not impact radiation-induced intestinal injury at 26 weeks.
This study supports a role for PAR2 activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacological PAR2 antagonists may have the potential to reduce intestinal side effects of radiation therapy and/or as countermeasures in radiological accidents or terrorism scenarios.