title: Inhibition of protease-activated receptor 1 ameliorates intestinal radiation mucositis in a preclinical rat model.
abstract: OBJECTIVE
  To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects.
  
  
  METHODS
  Rats underwent fractionated X-irradiation (5 Gy×9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation.
  
  
  RESULTS
  Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups.
  
  
  CONCLUSIONS
  Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.
authors.affiliation: Division of Radiation Health, University of Arkansas for Medical Sciences, Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.forename: Ashwini
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
authors.forename: Louis M
authors.initials: LM
authors.lastname: Fink
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D005355:Fibrosis; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D052016:Mucositis / Q000209:etiology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000150:complications / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010975:Platelet Aggregation Inhibitors
chemical_list: D001572:Benzofurans; D002219:Carbamates; D018809:Proliferating Cell Nuclear Antigen; D011837:Radiation-Protective Agents; C578350:SCH602539; D009195:Peroxidase; D010975:Platelet Aggregation Inhibitors