Factors involved in fibrosis of colorectal tissue due to chronic ulcerative colitis

Abstract

Background & Aim: Chronic and persistent inflammation such as in ulcerative colitis and Crohn's disease may lead to excessive fibrosis of the intestine, which may cause intestinal dysfunction, intestinal stricture, and persistent diarrhea. Focusing on the regulation of inflammation, repair and regeneration of intestinal tissues, and fibrosis will lead to the proposal of a new treatment for ulcerative colitis. In this study, we established an experimental model of colorectal fibrosis using a mouse model of ulcerative colitis induced with dextran sulfate sodium (DSS). In addition, since the TGF-β signaling pathway, one of the important pathways for fibrotic diseases, interacts with the SMAD pathway, the Ras/MEK-ERK pathway, and the Rho-ROCK pathway, statin drugs that inhibit the Ras and Rho pathways may be useful against fibrotic diseases. Therefore, we administered pravastatin to a model of fibrosing enterocolitis and investigated its pathophysiological effects. Materials & Methods: Male C57BL/6N mice were given DSS ad libitum for 7 days, followed by a 14-day rest period (drinking sterile water). This was repeated for one cycle up to a maximum of three cycles. Body weight and fecal condition were measured and expressed as Disease Activity Index (DAI) to analyze the degree of inflammation. Hematoxylin and eosin staining was performed for histological examination. On Day 63, Masson trichrome and picrosirius red staining and immunostaining with periostin antibody were performed to examine the degree of fibrosis. Expression of SMAD3, SMAD4, TIMP-1, and Rock1/RhoA were analyzed by western blotting. Fourteen-day rest period following the third DSS drinking (Day 49-Day 63), pravastatin was administered orally once daily for 14 days. Results: In the DSS drinking group, DAI increased, colon length shortened, and wet weight per cm of colon increased. HE staining showed lymphocyte infiltration in the mucosal and submucosal tissues, Masson trichrome staining showed increased collagen fibers, and picrosirius red staining showed increased type I collagen in the submucosal tissue and a marked increase in type III collagen in the mucosal layer. Immunohistochemical staining showed increased periostin expression. Pravastatin treatment had no effect on DAI, colon length, or wet weight per cm of colon compared to the vehicle group. Significant increases in collagen fibers, type I collagen in submucosal tissue, as well as periostin were observed in the pravastatin group, as in the vehicle group. On Day 63, increased expression of p-SMAD3, SMAD4, TIMP-1, and Rock1/RhoA was observed, and in the pravastatin group, p-SMAD3 expression was further increased and the percentage of Rock1/RhoA expression was significantly decreased compared to the vehicle group. Conclusion: Repeated treatment with DSS was shown to cause exacerbation of colitis with lymphocytic infiltration and fibrosis with increased type I collagen and TIMP expression in the colonic submuc The authors declare no conflict of interest. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.