Effect And Mechanism Of Simvastatin On Colonic Fibrosis In Rats With Crohn’s Disease

BackgroundCrohn’s disease (CD) is a unknown etiology of chronic and non-specificinflammation and granulomatosis of the gastrointestinal tract, that chronic diseaseprocess may result in a variety of complications. Intestinal fibrosis or stenosis is oneof common and serious complications. More than one-third of patients with CDdevelop distinct intestinal fibrosis and stricture that result in surgical treatment, andapproximately40%of patients with intestinal resection have the recurrence ofintestinal stenosis after4years. Currently there are no effective preventive ortherapeutic interventions for intestinal fibrosis. It is reported that statins,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, exhibitantifibrotic properties in models of fibrotic disease in the kidney, heart, lung and skin,and can inhibit the inflammatory response in CD, in addition to the effect oflipid-lowering. However, there is rare report concerning its role in intestinal fibrosiswith CD.ObjectiveTo investigate the efficacy and mechanism of simvastatin on colonic fibrosis inrat with Crohn’s disease.Methods1.Crohn’s disease (CD) model was established in rats with intracolonicadministration of2,4,6-trinitrobenzene sulphonic acid(TNBS). Animals in the controlgroup were given an enema of the same volume of0·9%saline instead of TNBS.2. Forty-eight healthy male Sprague-Dawley rats were divided six groups(n=8):control group, TNBS group, treatment groupⅠ and Ⅱ(from0to21days after induction of TNBS, simvastatin,5and20mg/kg.d), treatment group Ⅲ and Ⅳ(from7to21days after induction of TNBS, simvastatin,5and20mg/kg.d).3. Body weight and disease activity index(DAI) of the rats were evaluated, andcolon length and weight were also measured. The colonic tissues weremacroscopically and histologically examined.4. Reverse transcription polymerase chain reaction (RT-PCR) was used to detectthe mRNA expression of collagen types I, Fibronectin(FN) and connective tissuegrowth factor (CTGF). Western blotting was used to detect the protein expression ofcollagen types I, FN, CTGF and p-MYPT-1(representing activity of Rho kinase).Results1. In comparison with control group, the body weight and colon length weredecreased while colon weight and DAI score were increased obviously in TNBSgroup(P<0.01), the scores of macroscopic and micrpscopic colonic damage andfibrosis were significantly higher(P<0.01), as well as expressions of collagen I,FN,CTGF and p-MYPT-1in colonic tissu in TNBS group(P<0.01).2. After intervention of simvastatin, body weight was increased(P>0.05), andcolon length and weight were improved comparison with TNBS group(P<0.05). Thescores of macroscopic and micrpscopic colonic damage and fibrosis, and theexpressions of collagen I, FN, CTGF and p-MYPT-1in colonic tissue were notablyreduced compared with TNBS group(all P values<0.05). All above parameters werenot statistically significant among all treatment groups (all P values>0.05).Conclusions1. Simvastatin can reduce the content of extracellular matrix in colonic fibrosis ratwith TNBS-induced colitis, and is effective in preventing from colonic fibrosis.2. The antifibrotic mechanism of simvastatin may result from inhibition ofactivity of Rho-kinase, effect Rho kinase (Rock) signal pathway, and down-regulatethe over-expression of CTGF.