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P056. GED-0507–34 Levo, a novel modulator of PPARgamma as new therapeutic strategy in the treatment of intestinal fibrosis

S. Speca1, C. Rousseaux1, C. Dubuquoy1, A. Vetuschi2, R. Sferra3, B. Bertin4, L. Dubuquoy1, E. Gaudio5, S. Bellinvia6, P. Desreumaux1, G. Latella3, 1INSERM U995, Lille, France, 2University of L'Aquila, L'aquila, Italy, 3University of L'Aquila, L'Aquila, Italy, 4University Lille 2, Lille, France, 5University “Tor Vergata” of Roma, Roma, Italy, 6Giuliani Pharma, Milano, Italy

Background

Intestinal fibrosis is a progressive and uncontrolled deposition of extracellular matrix components (ECM) mainly associated to Crohn's disease (CD) and for which efficient and well-tolerated therapies are not yet available. An optimal target for new therapeutic anti-fibrotic strategies is represented by peroxisome proliferator-activated receptors (PPAR)gamma, an antagonist of TGFbeta/Smad, the key profibrotic pathway. Aim: to evaluate the effect of GED, a new PPARgamma modulator (1) in vivo to inhibit DSS-induced colonic fibrosis in mice and (2) in vitro to prevent the differentiation of human colonic fibroblasts and epithelial cells into myofibroblasts.

Methods

Chronic colonic fibrosis was induced in C57BL/6 mice by successive 2.5% (w/v) DSS administration in drinking water for 6 weeks. After 6 weeks, the therapeutic effect of GED (30 mg/kg/d), daily administered by oral gavage, was assessed macroscopically (weight/length of the colon, edema, ulcers, adhesions, thickness, dilatation), histologically (inflammatory infiltrate, collagen deposition) and biologically (colonic alpha-SMA, collagen I, TGFbeta1, CTGF, Smad3 and IL-13, by immunohistochemistry and immunoblotting). Differentiation of fibroblasts and intestinal epithelial cells (IECs) into myofibroblasts was induced by 4 day of TGF-beta administration (1 ng/mL and 10 ng/mL, respectively). Expression of aplha-SMA, fibronectine and the specific IECs markers (A33 and cytokeratin) was evaluated by quantitative RT-PCR. In vitro collagen deposition was observed by Picrosirius red staining.

Results

In DSS-treated mice GED induced a significant 26% decrease of the colon weight/length ratio (p < 0.05) and ameliorated macroscopic and microscopic lesions determining 35% reduction of total macroscopic score (p < 0.05) and 91% (p < 0.01) of histological score. GED regulated the increased DSS-induced tissue expression of specific fibrotic markers, mainly Collagen I-III (48% p < 0.05), CTGF (35%, p < 0.05) and IL-13 (50%, p < 0.01). GED reduced mRNA expression of differentiation markers of fibroblasts and IECs, alpha-SMA (18%, p < 0.05 and 16%, p < 0.05, respectively) and fibronectine (45%, p < 0.005 and 67%, p < 0.005, respectively) and restored specific IECs markers. GED determined a 65% reduction of TGFbeta-induced collagen deposition (p < 0.05), both in fibroblast and IECs.

Conclusion

GED ameliorates the intestinal fibrosis in a DSS-induced chronic colitis in mice by controlling the main molecular and cellular mechanisms involved.