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.