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
2023-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.