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P063 Dissecting the role of rage in intestinal fibrosis

S. Speca*1, M. Body-Malapel1, C. Fradin1, M. Djouina1, E. Boulanger1, A.-M. Schmidt2, P. Desreumaux1, C. Vignal1

1Centre Hospitalier Régional Universitaire de Lille, Lille, France, 2NYU Langone Medical Centre, Departments of Medicine (Endocrinology Div), Biochemistry and Molecular Pharmacology and Pathology (Pathology) , New York, United States

Background

The receptor for advanced glycation products (RAGE) is a member of the immunoglobulin superfamily able to regulate chronic inflammation. The prolonged AGE exposition in kidney, liver, and lung induces up regulation of alphaSMA, the main marker of myofibroblasts activation, resulting in an accumulation of extracellular matrix components (ECM) and consequent fibrosis. At intestinal level fibrosis is a common and severe compliance of inflammatory bowel disease (IBD), and inflamed colonic mucosa of patients with active IBD shows a significant increase of AGE and RAGE. Our aim was to determine the role of RAGE in intestinal fibrosis.

Methods

Fibrosis was induced in C57BL/6 wild-type (WT) and RAGE-/- mice by for 3 cycles of 2,5% (w/v) dextran sulfate sodium (DSS) administration for 6 weeks, macroscopic (including dilation, thickness, and adhesion) and microscopic lesions (inflammation by Hematoxylin/Eosin and collagen deposition by Picrosirius red staining) were scored for all colonic specimens. mRNA expression of the main profibrotic mediator, TGF-beta (Tgf-beta1 gene), alphaSMA (ACTA-1 gene), and the expression of ECM components, mainly collagen types I-III (Col1A1 gene) and fibronectin (FN-1 gene), was evaluated by quantitative RT-polymerase chain reaction (PCR). Moreover, RAGE gene expression levels were evaluated in TGF-beta-stimulated intestinal fibroblasts and epithelial cells, as well as in human primary intestinal fibroblasts isolated from IBD patients

Results

Compared with WT mice, DSS-treated C57/Bl6 RAGE-/- mice showed a lower colon weight/length ratio (29%, p < 0.0001), an indicator of wall thickening. In RAGE-/-mice, the macroscopic score was significantly reduced compared with WT mice (6 ± 0.92 vs 1.43 ± 0.54, p < 0.0001). DSS-treated RAGE-/- mice showed less then 50% (p < 0.001) of total microscopic score valued in WT mice. DSS administration also induced significant increase of Tgf-beta1, ACTA-1, Col1A1, and FN-1 gene expression in WT mice colon. DSS-treated RAGE-/- mice showed lower expression of Col1A1 (3.17 fold, p < 0.01), Tgf-beta1 (2 fold, p < 0.01), ACTA-1 (1.2 fold, p < 0.05) than WT mice, whereas FN-1 expression was totally prevented. In addition, myofibroblasts deriving by TGF-beta-treated intestinal fibroblasts and epithelial cells showed enhanced mRNA RAGE expression by 1.5 fold (p < 0.01) and 2.3 fold (p < 0.01), respectively. Additionally, in primary human intestinal fibroblasts, obtained by UC patients, a significant increase by 3.8 fold (p < 0.05) of RAGE gene expression was observed.

Conclusion

The potential profibrotic role of RAGE in the development of intestinal fibrosis could shed light into the complex and dynamic fibrogenic processes in IBD.