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Heparan mimetic regulates collagen expression and TGF-ß1 distribution in gamma-irradiated human intestinal smooth muscle cells

CRRET/CNRS UPRESA 7053, Faculté des Sciences de Créteil, Université PARIS-12, France; and
^* Institut de Protection et de Sûreté Nucléaire, Département de Protection de la Santé de l’Homme et de Dosimétrie, Section Autonome de Radiobiologie Appliquée à la Médecine, IPSN, BP no. 6, F-92265 Fontenay aux Roses Cedex, France

¹Correspondence: CRRET-CNRS UPRESA 7053, Faculté des Sciences de Créteil, Université Paris 12, Avenue du Général de Gaulle, 94010 Créteil cedex, France. E-mail: Barritault{at}univ-paris12.fr

Radiation-induced intestinal fibrosis is characterized by collagen accumulation, a process in which TGF-ß1 plays a key role. We analyzed the effects of gamma radiation on collagen expression and TGF-ß1 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 ⁶⁰Co irradiation (10 Gy), HISM were labeled with [³H] proline (±RG-1503). Radiolabeled collagen I, III, and V were quantified by SDS-PAGE. TGF-ß1 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-ß1 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-ß1 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-ß1 distribution. The antifibrotic RG-1503 restored HISM physiological characteristics and may represent a promising therapeutic approach for radiation-induced intestinal fibrosis.—Alexakis, C., Guettoufi, A., Mestries, P., Strup, C., Mathé, D., Barbaud, C., Barritault, D., Caruelle, J.-P., Kern, P. Heparan mimetic regulates collagen expression and TGF-ß1 distribution in gamma-irradiated human intestinal smooth muscle cells.

Key Words: gamma radiation • intestinal fibrosis • collagen • transforming growth factor ß1

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