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Canadian Journal of Gastroenterology
Volume 26, Issue 1, Pages 33-39
http://dx.doi.org/10.1155/2012/628268
Original Article

Losartan Reduces Trinitrobenzene Sulphonic Acid-Induced Colorectal Fibrosis in Rats

Dov Wengrower,1 Giuliana Zanninelli,2 Giovanni Latella,2 Stefano Necozione,3 Issa Metanes,1 Eran Israeli,1 Joseph Lysy,1 Mark Pines,4 Orit Papo,5 and Eran Goldin1

1Institute of Gastroenterology, Hadassah University Hospital, Jerusalem, Israel
2Gastroenterology Unit, University of L’Aquila, L’Aquila, Italy
3Clinical Epidemiology Unit, Department of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy
4Institute of Animal Science, The Volcani Center, Bet Dagan, Israel
5Department of Pathology, Hadassah University Hospital, Jerusalem, Israel

Received 5 March 2011; Accepted 25 March 2011

Copyright © 2012 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Intestinal fibrosis – a chronic and progressive process mediated by several factors – occurs in several fibrostenosing enteropathies, but most frequently in patients with Crohn’s disease (CD). Despite the advances made in the understanding of CD and its management over the past 20 years, surgical intervention remains the only treatment strategy for patients with fibrostenosing CD. The results of several studies, however, have suggested that fibrosis may be a reversible and/or preventable phenomenon. Following an overview summarizing the contemporary knowledge regarding the cellular, cytokine and growth factor interactions that contribute to inflammation and the progression of fibrosis, this article describes an experimental animal model of colitis resembling human CD, which the authors used to investigate whether losartan, an angiotensin II receptor antagonist, could be used as a prophylactic agent to reduce the risk of intestinal fibrosis and strictures in patients with CD.

BACKGROUND: Intestinal fibrosis is a challenging clinical condition in several fibrostenosing enteropathies, particularly Crohn’s disease. Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis. Fibrosis, due to an abnormal accumulation of extracellular matrix proteins, is a chronic and progressive process mediated by cell/matrix/cytokine and growth factor interactions, but may be a reversible phenomenon. Of the several molecules regulating fibrogenesis, transforming growth factor-beta 1 (TGF-β1) appears to play a pivotal role; it is strongly induced by the local activation of angiotensin II. The levels of both TGF-β1 and angiotensin II are elevated in fibrostenosing Crohn’s disease.

AIMS: To evaluate the in vivo effect of losartan – an angiotensin II receptor antagonist – on the course of chronic colitis-associated fibrosis and on TGF-β1 expression.

METHODS: Colitis was induced by intrarectal instillation of trinitrobenzene sulphonic acid (TNBS) (15 mg/mL) while losartan was administered orally daily by gavage (7 mg/kg/day) for 21 days. Three groups of rats were evaluated: control (n=10); TNBS treated (n=10); and TNBS + losartan treated (n=10). Inflammation and fibrosis of the colon were evaluated by macro- and microscopic score analysis. Colonic TGF-β1 levels was measured using ELISA.

RESULTS: Twenty-one days after induction, losartan significantly improved the macro- and microscopic scores of fibrosis in the colonic wall and reduced TGF-β1 concentration.

CONCLUSIONS: Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-β1 expression.