Increased activation of latent TGF-?1 by ?V?3 in human Crohn's disease and fibrosis in TNBS colitis can be prevented by cilengitide.

ABSTRACT: Strictures develop in >30% of patients affected with Crohn's disease. No available medication prevents stricture development in susceptible patients. In Crohn's strictures, but not adjacent normal intestine, TGF-?1 increases in muscularis smooth muscle, increasing collagen I production and strictures. Muscle cells express ?V?3 integrin containing an Arg-Gly-Asp (RGD) binding domain. The aim was to determine whether increased TGF-?1 levels in strictures were the result of latent TGF-?1, which contains an RGD sequence, binding to and activation by ?V?3; and whether cilengitide, which is an RGD-containing ?V?3 integrin inhibitor, decreases TGF-?1 activation and development of fibrosis in chronic 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis.Muscle cells isolated from Crohn's disease strictures and normal resection margin and from the colon of rats after 42 days of chronic TNBS-induced colitis were used to prepare RNA and protein lysates and to initiate primary cultures. The mechanisms leading to increased TGF-?1 activation, collagen I production, and fibrosis were examined in human muscle and in rats. Human cultured cells in vitro and rats in vivo were treated with cilengitide to determines it efficacy to decrease TGF-?1-activation, collagen production, and decrease the development of fibrosis.Latent TGF-?1 is activated by the ?V?3 RGD domain in human and rat intestinal smooth muscles. Increased activation of TGF-?1 in Crohn's disease and in TNBS-induced colitis causes increased collagen production, and fibrosis that could be inhibited by cilengitide.Cilengitide, an ?V?3 integrin RGD inhibitor, could be a novel treatment to diminish excess TGF-?1 activation, collagen I production, and development of fibrosis in Crohn's disease.

SUBMITTER: Li C 

PROVIDER: S-EPMC3889641 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature