title: Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis.
abstract: BACKGROUND
  Intestinal fibrosis is mainly associated with Crohn's disease and is defined as a progressive and excessive deposition of extracellular matrix components. No specific antifibrotic therapies are available. In this study, we evaluate the antifibrotic effect of a novel 5-ASA analog able to activate the peroxisome proliferator-activated receptor γ, named GED-0507-34 Levo.
  
  
  METHODS
  Colonic fibrosis was induced in 110 C57BL/6 mice by 3 cycles of 2.5% (wt/vol) dextran sulfate sodium administration for 6 weeks. The preventive effects of oral daily GED (30 mg · kg(-1) · d(-1)) administration were evaluated using a macroscopic and histological score and also through biological endpoints. Expression of main markers of myofibroblasts activation was determined in transforming growth factor (TGF-β)-stimulated intestinal fibroblasts and epithelial cells.
  
  
  RESULTS
  GED improved macroscopic and microscopic intestinal lesions in dextran sulfate sodium-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) and the main TGF-β/Smad pathway components. GED also decreased the interleukin-13 and connective tissue growth factor 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 intestinal epithelial cell lines, by regulating mRNA expression of α-SMA and fibronectin, and restoring the TGF-β-induced loss of intestinal epithelial cell markers. GED treatment also reduced the TGF-β and ACTA1 expression in primary human intestinal fibroblasts from ulcerative colitis patients.
  
  
  CONCLUSIONS
  GED ameliorates intestinal fibrosis in dextran sulfate sodium-induced chronic colitis in mice and regulates major profibrotic cellular and molecular mechanisms.
authors.affiliation: *Inserm, LIRIC UMR995, Lille, France; †CHRU de Lille, Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, LIRIC, UMR995, Lille, France; ‡Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy; §IBD, Lille, France; ‖Department of Pathobiology, Lerner Research Institute, and Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio; ¶Université Lille Nord de France, Lille, France; and **Department of Human Anatomy, University of Roma "La Sapienza," Roma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Speca
authors.forename: Christel
authors.initials: C
authors.lastname: Rousseaux
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubuquoy
authors.forename: Florian
authors.initials: F
authors.lastname: Rieder
authors.forename: Antonella
authors.initials: A
authors.lastname: Vetuschi
authors.forename: Roberta
authors.initials: R
authors.lastname: Sferra
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giusti
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bertin
authors.forename: Laurent
authors.initials: L
authors.lastname: Dubuquoy
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Giovanni
authors.initials: G
authors.lastname: Latella
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003092:Colitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000150:complications* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000588557:3-(4-aminophenyl)-2-methoxypropionic acid; D000814:Aniline Compounds; D047495:PPAR gamma; D010666:Phenylpropionates; D012333:RNA, Messenger