Objective Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. Methods Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague-Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-beta) signalling [TGF-beta, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested. Key findings Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-beta expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression. Conclusions Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-beta signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-beta/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.

Role of cyclooxygenase pathways in bowel fibrotic remodelling in a murine model of experimental colitis

Colucci, Rocchina
;
Fornai, Matteo;Antonioli, Luca;Segnani, Cristina;Ippolito, Chiara;Pellegrini, Carolina;Blandizzi, Corrado;Bernardini, Nunzia
2022-01-01

Abstract

Objective Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. Methods Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague-Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-beta) signalling [TGF-beta, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested. Key findings Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-beta expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression. Conclusions Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-beta signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-beta/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.
2022
Colucci, Rocchina; Fornai, Matteo; Antonioli, Luca; Segnani, Cristina; Ippolito, Chiara; Pellegrini, Carolina; Nericcio, Anna; Zizzo, Maria Grazia; Se...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1161426
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