title: Recombinant Thrombomodulin (Solulin) Ameliorates Early Intestinal Radiation Toxicity in a Preclinical Rat Model.
abstract: Intestinal radiation toxicity occurs during and after abdominopelvic radiotherapy. Endothelial cells play a significant role in modulating radiation-induced intestinal damage. We demonstrated that the endothelial cell surface receptor thrombomodulin (TM), a protein with anticoagulant, anti-inflammatory and antioxidant properties, mitigates radiation-induced lethality in mice. The goal of this study was to determine whether recombinant TM (Solulin) can protect the intestine from toxicity in a clinically relevant rat model. A 4 cm loop of rat small bowel was exposed to fractionated 5 Gy X radiation for 9 consecutive days. The animals were randomly assigned to receive daily subcutaneous injections of vehicle or Solulin (3 mg/kg/day or 10 mg/kg/day) for 27 days starting 4 days before irradiation. Early intestinal injury was assessed two weeks after irradiation by quantitative histology, morphometry, immunohistochemistry and luminol bioluminescence imaging. Solulin treatment significantly ameliorated intestinal radiation injury, made evident by a decrease in myeloperoxidase (MPO) activity, transforming growth factor beta (TGF-β) immunoreactivity, collagen-I deposition, radiation injury score (RIS) and intestinal serosal thickening. These findings indicate the need for further development of Solulin as a prophylactic and/or therapeutic agent to mitigate radiation-induced intestinal damage.
authors.affiliation: a Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.affiliation: a Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Junru
authors.initials: J
authors.lastname: Wang
authors.affiliation: a Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Sarita
authors.initials: S
authors.lastname: Garg
authors.affiliation: a Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas;
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.affiliation: b PAION Deutschland GmbH, Aachen, Germany; and.
authors.forename: Karl-Uwe
authors.initials: KU
authors.lastname: Petersen
authors.affiliation: a Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas;|c Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000528:radiation effects*; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000528:radiation effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D018180:Thrombomodulin / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D018180:Thrombomodulin; D016212:Transforming Growth Factor beta; D003094:Collagen; D009195:Peroxidase