skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

Purpose: Protease-activated receptor-2 (PAR{sub 2}) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR{sub 2} 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 PAR{sub 2} activation. Methods and Materials: Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR{sub 2} agonist (2-furoyl-LIGRLO-NH{sub 2}) 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 PAR{sub 2} agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR{sub 2} 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 PAR{sub 2} agonist also exacerbated the radiation injury score, serosal thickening, and mucosal inflammation (p <.05) in the beforemore » and before-after groups. The short-term exogenous activation of PAR{sub 2} did not affect radiation-induced intestinal injury at 26 weeks. Conclusion: The results of the present study support a role for PAR{sub 2} activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR{sub 2} antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.« less

Authors:
; ;  [1];  [2];  [3];  [1];  [4]
  1. Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR (United States)
  2. Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB (Canada)
  3. (Canada)
  4. (United States)
Publication Date:
OSTI Identifier:
21451138
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 77; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2009.12.075; PII: S0360-3016(10)00114-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; 62 RADIOLOGY AND NUCLEAR MEDICINE; INTESTINES; PEPTIDES; RADIATION INJURIES; RADIOTHERAPY; RATS; RECEPTORS; ANIMALS; BIOLOGICAL EFFECTS; BIOLOGICAL RADIATION EFFECTS; BODY; DIGESTIVE SYSTEM; DISEASES; GASTROINTESTINAL TRACT; INJURIES; MAMMALS; MEDICINE; MEMBRANE PROTEINS; NUCLEAR MEDICINE; ORGANIC COMPOUNDS; ORGANS; PROTEINS; RADIATION EFFECTS; RADIOLOGY; RODENTS; THERAPY; VERTEBRATES

Citation Formats

Wang Junru, Boerma, Marjan, Kulkarni, Ashwini, Hollenberg, Morley D., Department of Medicine, University of Calgary, Calgary, AB, Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.ed, and Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR. Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine. United States: N. p., 2010. Web. doi:10.1016/j.ijrobp.2009.12.075.
Wang Junru, Boerma, Marjan, Kulkarni, Ashwini, Hollenberg, Morley D., Department of Medicine, University of Calgary, Calgary, AB, Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.ed, & Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR. Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine. United States. doi:10.1016/j.ijrobp.2009.12.075.
Wang Junru, Boerma, Marjan, Kulkarni, Ashwini, Hollenberg, Morley D., Department of Medicine, University of Calgary, Calgary, AB, Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.ed, and Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR. Thu . "Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine". United States. doi:10.1016/j.ijrobp.2009.12.075.
@article{osti_21451138,
title = {Activation of Protease Activated Receptor 2 by Exogenous Agonist Exacerbates Early Radiation Injury in Rat Intestine},
author = {Wang Junru and Boerma, Marjan and Kulkarni, Ashwini and Hollenberg, Morley D. and Department of Medicine, University of Calgary, Calgary, AB and Hauer-Jensen, Martin, E-mail: mhjensen@life.uams.ed and Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR},
abstractNote = {Purpose: Protease-activated receptor-2 (PAR{sub 2}) is highly expressed throughout the gut and regulates the inflammatory, mitogenic, fibroproliferative, and nociceptive responses to injury. PAR{sub 2} 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 PAR{sub 2} activation. Methods and Materials: Rat small bowel was exposed to localized single-dose radiation (16.5 Gy). The PAR{sub 2} agonist (2-furoyl-LIGRLO-NH{sub 2}) 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 PAR{sub 2} agonist did not elicit changes in the unirradiated (shielded) intestine. In contrast, in the irradiated intestine procured 2 weeks after irradiation, administration of the PAR{sub 2} 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 PAR{sub 2} 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 PAR{sub 2} did not affect radiation-induced intestinal injury at 26 weeks. Conclusion: The results of the present study support a role for PAR{sub 2} activation in the pathogenesis of early radiation-induced intestinal injury. Pharmacologic PAR{sub 2} antagonists might have the potential to reduce the intestinal side effects of radiotherapy and/or as countermeasures in radiologic accidents or terrorism scenarios.},
doi = {10.1016/j.ijrobp.2009.12.075},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 4,
volume = 77,
place = {United States},
year = {2010},
month = {7}
}