Heparan mimetic regulates collagen expression and TGF‐β1 distribution in gamma‐irradiated human intestinal smooth muscle cells

Abstract

Radiation-induced intestinal fibrosis is characterized by collagen accumulation, a process in which TGF-beta1 plays a key role. We analyzed the effects of gamma radiation on collagen expression and TGF-beta1 distribution in human intestinal smooth muscle cells (HISM). We investigated the activity of a carboxymethylated and sulfated dextran (RG-1503), exhibiting antifibrotic properties and promoting in vivo intestinal tissue repair, on irradiated HISM. After (60)Co irradiation (10 Gy), HISM were labeled with [(3)H] proline (+/-RG-1503). Radiolabeled collagen I, III, and V were quantified by SDS-PAGE. TGF-beta1 was quantified by ELISA in culture medium, pericellular and intracellular compartments. Irradiation induced a specific 2.85-fold increase in collagen III production by HISM. Collagen V decreased by 80% 72 h after irradiation. Pericellular TGF-beta1 was increased (up to twofold) in irradiated HISM. RG-1503 added before or after irradiation reversed both mRNA and protein levels of collagen III and V to control values. RG-1503 decreased the amount of TGF-beta1 in the cell layer below the control values. Irradiation of HISM induced the development of a fibrotic phenotype in terms of collagen production and TGF-beta1 distribution. The antifibrotic RG-1503 restored HISM physiological characteristics and may represent a promising therapeutic approach for radiation-induced intestinal fibrosis.

Fucoidan Modulates the Effect of Transforming Growth Factor (TGF)-.BETA.1 on Fibroblast Proliferation and Wound Repopulation in in Vitro Models of Dermal Wound Repair

“…38) whereas another study has shown that a heparin mimic can inhibit the fibrotic effects of TGF-b 1 . 39) Interpretation of our data is further complicated by work of Schmidt et al 40) which showed that a heparin-like molecule can induce increased expression of TGF-b in coronary smooth muscle cells which was associated with the expected inhibition of cell proliferation. Our study differs from those discussed here in a number of respects, not least the fact that our preparation of fucoidan is commercial and therefore very heterogenous and contains polymers with potentially differing properties.…”

RGTA OTR4120, a heparan sulfate mimetic, is a possible long‐term active agent to heal burned skin

“…RGTA induced ECM remodeling by decreasing the production of collagen III relative to other collagen types in smooth muscle cells. [17][18][19] In addition, RGTA restored a nearly normal pattern of collagen expression in biopsies from patients with Crohn's disease, specifically reducing the overexpression of collagen III by 75%. 13 Moreover, RGTA modulated the enzymatic activities of several proteases involved in ECM remodeling.…”

A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis

“…In addition, these polymers enhance in vitro endothelialization (22) of vascular prosthesis and partly prevent in vivo damage caused by skeletal muscle (23) and myocardial ischemia (24). RGTA interacts with and protects various HBGFs, such as fibroblast growth factor (FGF) and transforming growth factor ␤, against proteolytic degradation (25,26).…”