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To investigate whether targeting proteasome might reverse intestinal fibrosis in rats.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.TNBS-treated rats had a higher colon weight/length ratio compared to control rats (P0.01). Furthermore, fibrosis and inflammation scores were higher in TNBS-treated rats compared to control rats (P0.01 for both). Colonic production of TGF-β production tended to be higher in TNBS-treated rats (P0.06). Fibrosis-related proteins such as phospho-p38, phospho-SMAD2/3, and PPARγ were significantly higher in TNBS-treated rats compared to control rats (all P0.05). TNBS rats had a higher expression of Akt compared to control rats (P0.01). Tight junction proteins were modified by repeated TNBS challenge: colon occludin expression rose significantly (P0.01), whereas claudin-1 expression fell (P0.01). Bortezomib inhibition significantly decreased chymotrypsin-like activity (P0.05), but had no significant effect on trypsin-like activity (P0.05). In contrast, bortezomib had no effect on other studied parameters such as fibrosis score, TGF-β signaling, or tight junction expression (P0.05 for all).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.