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

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.

Automated summary

This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. The results showed that COX inhibitors can reverse the histological, molecular, and functional changes in the fibrotic colon. Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-beta signaling.