Heparan mimetic regulates collagen expression and TGF-beta1 distribution in gamma-irradiated human intestinal smooth muscle cells.
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.
Alexakis
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C
CRRET/CNRS UPRESA 7053, Faculté des Sciences de Créteil, Université PARIS-12, France.
Guettoufi
A
A
Mestries
P
P
Strup
C
C
Mathé
D
D
Barbaud
C
C
Barritault
D
D
Caruelle
J P
JP
Kern
P
P
D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000528:radiation effects*; D018716:Molecular Mimicry; D009130:Muscle, Smooth / Q000378:metabolism / Q000528:radiation effects*; D009844:Oligosaccharides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D003094:Collagen; D006497:Heparan Sulfate; D009844:Oligosaccharides; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C431384:RG 1503; C508960:TGFB1 protein, human