title: 2,4,6-trinitrobenzene sulfonic acid-induced chronic colitis with fibrosis and modulation of TGF-β1 signaling.
abstract: OBJECTIVE
  To investigate whether targeting proteasome might reverse intestinal fibrosis in rats.
  
  
  METHODS
  Chronic colitis was induced in rats by repeated administration of increasing dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 15, 30, 45, 60, 60, 60 mg) by rectal injection for 6 wk (from day 0 to day 35), while control rats received the vehicle. TNBS + bortezomib (BTZ) rats received intraperitoneal injections of BTZ twice weekly (from day 37 to day 44) at a dose of 25 mg/kg, whereas the control and TNBS groups received the same amount of the vehicle. Histologic scoring of inflammation and fibrosis was performed. Colonic production of transforming growth factor (TGF)-β was measured by ELISA. Colon fibrosis-related proteins such as phospho-p38, phospho-SMAD2/3, Akt and peroxisome proliferator activated receptor γ (PPARγ) were studied by western blot. Expression of the tight junction proteins, occludin and claudin-1, were assessed by Western blot. Colon proteasome activities (chymotrypsin-like and trypsin-like activities) were assessed.
  
  
  RESULTS
  TNBS-treated rats had a higher colon weight/length ratio compared to control rats (P < 0.01). Furthermore, fibrosis and inflammation scores were higher in TNBS-treated rats compared to control rats (P < 0.01 for both). Colonic production of TGF-β production tended to be higher in TNBS-treated rats (P < 0.06). Fibrosis-related proteins such as phospho-p38, phospho-SMAD2/3, and PPARγ were significantly higher in TNBS-treated rats compared to control rats (all P < 0.05). TNBS rats had a higher expression of Akt compared to control rats (P < 0.01). Tight junction proteins were modified by repeated TNBS challenge: colon occludin expression rose significantly (P < 0.01), whereas claudin-1 expression fell (P < 0.01). Bortezomib inhibition significantly decreased chymotrypsin-like activity (P < 0.05), but had no significant effect on trypsin-like activity (P > 0.05). In contrast, bortezomib had no effect on other studied parameters such as fibrosis score, TGF-β signaling, or tight junction expression (P > 0.05 for all).
  
  
  CONCLUSIONS
  Rats with TNBS-induced chronic colitis exhibited colon fibrosis associated with higher TGF-β signaling. Proteasome inhibition by bortezomib had no effect on fibrosis in our experimental conditions.
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Emilien
authors.initials: E
authors.lastname: Loeuillard
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bertrand
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Anni
authors.initials: A
authors.lastname: Herranen
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Melchior
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Guérin
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Moïse
authors.initials: M
authors.lastname: Coëffier
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Moutaz
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Savoye
authors.affiliation: Emilien Loeuillard, Julien Bertrand, Anni Herranen, Chloé Melchior, Charlène Guérin, Moïse Coëffier, Pierre Déchelotte, Guillaume Savoye, Rachel Marion-Letellier, INSERM Unit UMR1073, Rouen University and Rouen University Hospital, Rouen Cedex 76183, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Marion-Letellier
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D062725:Tight Junction Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; C508962:Tgfb1 protein, rat; D062725:Tight Junction Proteins; D053773:Transforming Growth Factor beta1; D000069286:Bortezomib; D014302:Trinitrobenzenesulfonic Acid; D046988:Proteasome Endopeptidase Complex
keywords: Bortezomib; Colitis; Fibrosis; Proteasome