Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis

Abstract

Background Intestinal fibrosis is mainly associated with Crohn's disease (CD) and is defined as a progressive and excessive deposition of extracellular matrix (ECM) components. No specific anti-fibrotic therapies are available. In this study we evaluate the anti-fibrotic effect of GED, a novel PPARγ modulator[1-4]. Methods Colonic fibrosis was induced in 110 C57BL/6 mice by three cycles of 2.5% (w/v) DSS administration for 6 weeks. The preventive effects of oral daily GED (30mg/kg/d) administration were evaluated using a macroscopic and histologic score as well as through biologic endpoints. Expression of main markers of myofibroblasts activation was determined in TGF-β-stimulated intestinal fibroblasts and epithelial cells (IECs). Results GED improved macroscopic and microscopic intestinal lesions in dextran sulfate sodium (DSS) treated animals and reduced the profibrotic gene expression of Acta2, COL1a1 and Fn1 by 1.48 folds (p< 0.05), 1.93 folds (p< 0.005) and 1.03 fold (p< 0.05), respectively. It reduced protein levels of main markers of fibrosis (α-SMA and Collagen I-II), as well as the main TGFβ/Smad pathway components. GED also decreased the IL-13 and CTGF expression by 1.89 folds (p<0.05) and 2.2 folds (p<0.005), respectively. GED inhibited TGF-β-induced activation of both fibroblast and IEC cell lines, by regulating mRNA expression of αSMA and fibronectin and restoring the TGF-β-induced loss of IEC markers. GED treatment also reduced the TGFB and ACTA1 expression in primary human intestinal fibroblasts from ulcerative colitis (UC) patients. Conclusions GED ameliorates intestinal fibrosis in DSS-induced chronic colitis in mice and regulates major pro-fibrotic cellular and molecular mechanisms.

Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor

“…Several drugs interfering directly with TGFb1 activity have been evaluated in pre-clinical IBD models of fibrosis, but with limited success. [27][28][29][30] However, given the pivotal anti-inflammatory properties of TGFb1, selective targeting of ROCK as a downstream mediator of TGFb signaling holds advantages over general TGFb inhibition. 31 Inhibition of ROCK by AMA0825 enhanced autophagy in fibroblasts both in vitro and ex vivo and contributed to the decrease in collagen and IL6 production in response to TGFb1.…”

Fibrostenotic strictures in Crohn’s disease

“…[137][138][139][140] However, classical 5-ASA does not appear to have anti-fibrotic activities in IBD, although a novel 5-ASA analog (GED), with strong affinity for peroxisome proliferator-activated receptor gamma (PPARγ) and potent anti-inflammatory properties greater than 5-ASA, has shown anti-fibrotic activity via PPARγ activation. 141 Corticosteroids are potent inhibitors of collagen synthesis in a variety of tissues, and its anti-fibrotic effects may inhibit wound healing. 25,142 However, methylprednisolone did not significantly reduce TGF-β1 levels or collagen content in TNBS-induced chronic colitis in rats.…”

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

“…Myofibroblasts isolated from intestinal strictures of CD patients overexpressed collagen III, and TGF-b1 promoted collagen III production by myofibroblasts [69]. Moreover, pirfenidone, an anti-fibrogenic drug used for the treatment of fibrotic diseases, suppressed intestinal fibrosis in a DSSinduced colitis model by inhibiting TGF-b signaling [70,71].…”