Modulation of the intestinal response to ionizing radiation by anticoagulant and non-anticoagulant heparins.
Endothelial dysfunction is involved in radiation responses in many normal tissues, including intestine. Endothelium-directed interventions ameliorate intestinal radiation injury (radiation enteropathy) in animal models, and anecdotal reports also suggest a beneficial effect of heparin. This study assessed low molecular weight heparin as an intestinal radiation response modifier. Rats underwent localized small bowel irradiation. Groups of rats were treated with saline, nadroparin (3 mg/kg/d), or a non-anticoagulant heparin (SR80258, 3 mg/kg/d), from 3 days before to 2 weeks after irradiation. The intestinal radiation response was assessed 2 weeks and 6 weeks after irradiation using quantitative histology; morphometry, and cellular and molecular end-points. Compared to vehicle-treated controls, nadroparin significantly exacerbated structural radiation injury, neutrophil infiltration, and TGFbeta and collagen I immunoreactivity levels 2 weeks after irradiation. SR80258 was associated with increased TGFbeta levels, but the other parameters did not reach statistical significance. At 6 weeks, structural, cellular, and molecular injury was similar in the three experimental groups. Heparin, in contrast to antiplatelet agents and direct thrombin inhibitors, does not ameliorate, but exacerbates acute intestinal radiation toxicity. These data underscore the importance of heparin as an inhibitor of physiological anti-inflammatory mechanisms during tissue injury, as well as the non-anticoagulant effects of heparin. Moreover, these data may have implications for the use of heparin during radiation therapy.
Wang
Junru
J
University of Arkansas for Medical Sciences, Little Rock, Arizona, USA.
Zheng
Huaien
H
Qiu
Xiaohua
X
Kulkarni
Ashwini
A
Fink
Louis M
LM
Hauer-Jensen
Martin
M
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004751:Enteritis / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D017762:Nadroparin / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017211:Treatment Failure
D000925:Anticoagulants; D024042:Collagen Type I; D024061:Collagen Type III; D017762:Nadroparin; D011506:Proteins; D012333:RNA, Messenger