WIN55,212-2 attenuates intestinal fibrosis in a DSS-induced mouse model

TL;DR

WIN55,212-2, a cannabinoid agonist, reduces intestinal fibrosis in a mouse model of inflammatory bowel disease by lowering fibrosis-related gene expression.

Contribution

WIN55,212-2 is shown to inhibit intestinal fibrosis by modulating fibrosis regulatory proteins in a DSS-induced mouse model.

Findings

WIN55,212-2 reduced ACTA2, COL1A1, FN1, and SMAD3 gene expression in mouse colonic mucosa by 51%, 44%, 60%, and 22%, respectively.

Human UC patients showed increased COL1A1 and SMAD3 expression compared to healthy controls.

WIN55,212-2 may serve as a potential therapeutic target for IBD patients at risk of intestinal fibrosis.

Abstract

Inflammatory bowel diseases (IBD) are often associated with intestinal fibrosis. There is increased interest in new methods for managing intestinal fibrosis, among which the endocannabinoid system (ECS) is an interesting therapeutic target. The primary purpose of the study was to evaluate the effect of CB1/2 agonist, WIN 55,212-2 (WIN) on expression of fibrosis regulatory proteins: alpha smooth muscle Actin 2 (ACTA2), Collagen I (COLIA1), Fibronectin 1 (FN1) and SMAD family member 3 (SMAD3) in a mice model of dextran sulfate sodium (DSS)-induced intestinal fibrosis.

Chronic intestinal fibrosis was induced by oral administration of 1.5% DSS in rotation with tap water for 3 weeks in three cycles. WIN was administered intraperitoneally, once daily starting from day 10th and continued every other day until day 77th. The expression of genes encoding ACTA2, COL1A1, FN1, SMAD3, Col1a1, Fn1 both in mouse and human colon, was assessed with real-time PCR.

We found lower relative expression of genes encoding fibrosis regulatory proteins in colonic mucosa of mice treated with WIN than in inflamed mice: ACTA2 (–51%), COL1A1 (–44%), FN1 (–60%), and SMAD3 (–22%). Human colonic mucosal patients with UC showed higher expression of COL1A1 (+ 57%) and SMAD3 (+ 34%) compared to healthy controls.

Our results show that regulation of ECS activity may play a role in the inhibition of intestinal fibrosis in IBD and appears as a potential therapeutic target in patients at high risk of developing strictures.

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