Heparin and low-molecular-weight heparin (enoxaparin) significantly ameliorate experimental colitis in rats.
OBJECTIVE
The anticoagulants, unfractionated heparin and low-molecular-weight heparin, demonstrated anti-inflammatory effects in animal models and in humans. Because of its dual effects, high-dose heparin was proposed as a therapeutic modality for ulcerative colitis. We investigated whether a low dose of low-molecular-weight heparin-enoxaparin (Clexane, Rhône-Poulenc Rorer, France)-ameliorates the inflammatory response in two models of experimental colitis.


METHODS
Colitis was induced in rats by intrarectal administration of dinitrobenzene sulphonic acid. Enoxaparin (40, 80 and 200 microg/kg) or unfractionated heparin (100, 200 and 400 U/kg) were administered subcutaneously immediately after the induction of damage. Enoxaparin, 80 microg/kg, was also administered after induction of colitis by intrarectal administration of iodoacetamide. Rats were sacrificed 1, 3 or 7 days after induction of injury. Colonic damage was assessed macroscopically and histologically. Mucosal prostaglandin E2 generation, myeloperoxidase and nitric oxide synthase activities and tumour necrosis factor-alpha levels in blood were determined.


RESULTS
Enoxaparin and heparin significantly ameliorated the severity of dinitrobenzene sulphonic acid- and iodoacetamide-induced colitis as demonstrated by a decrease in mucosal lesion area, colonic weight and mucosal myeloperoxidase and nitric oxide synthase activities. The dose-response curve had a bell-shaped configuration: enoxaparin, 80 microg/kg, and unfractionated heparin, 200 U/kg, were the optimal doses.


CONCLUSIONS
Low-dose enoxaparin and unfractionated heparin ameliorate the severity of experimental colitis. This effect is related to their anti-inflammatory rather than anticoagulant properties.
Dotan
I
I
Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. iris_dotan@smtplink.mssm.edu
Hershkoviz
R
R
Karmeli
F
F
Brazowski
E
E
Peled
Y
Y
Rachmilewitz
D
D
Halpern
Z
Z
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000925:Anticoagulants / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D007460:Iodoacetamide / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D001557:Benzenesulfonates; D017984:Enoxaparin; D014409:Tumor Necrosis Factor-alpha; C007488:dinitrobenzenesulfonic acid; D006493:Heparin; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D007460:Iodoacetamide