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P017. Prostaglandin E2 regulates intestinal inflammation and modifies in vivo and in vitro extracellular matrix regulation

P017. Prostaglandin E2 regulates intestinal inflammation and modifies in vivo and in vitro extracellular matrix regulation

A.C. Chew1, F. Lloyd1, I.C. Lawrance1

1University of Western Australia, Centre for Inflammatory Bowel Diseases, School of Medicine and Pharmacology, School of Medicine and Pharmacology, Fremantle, Australia

Background: The chronic intestinal inflammation observed in the inflammatory bowel diseases can induce fibrosis and stricture formation. This study investigated the effect of prostaglandin E2 (PGE2) on inflammation and extracellular matrix (ECM) regulation in the murine model of 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced intestinal inflammation and fibrosis and ECM gene expression in human intestinal fibroblasts.

Methods: C57bl6 mice received TNBS enemas weekly for 2 or 6 weeks, ± indomethacin (Indo) (0.2 mg/kg/day/orally), ± PGE2 (10 mg/kg/day/orally) or a combination of Indo/PGE2. Inflammation and fibrosis was assessed histologically. The human colonic fibroblast cell line, CCD-18co, was stimulated with PMA (10 ng/µl) for 24hrs prior to treatment with Indo (50 µM), PGE2 (50 µM) or a combination of Indo/PGE2. mRNA was isolated and collagen 1 (Col1), MMP‑1, TIMP‑1 and TGF‑β1 expression levels assessed by RT-qPCR.

Results: At 2 weeks compared to TNBS alone, mice treated with Indo/TNBS had significantly more inflammation and fibrosis (p = 0.004 and 0.00004), while those receiving PGE2/TNBS had significantly less inflammation (p < 0.05) and fibrosis (p < 0.05). At 6 weeks compared to TNBS alone, inflammation and fibrosis was not different in the Indo/TNBS-treated animals, but PGE2/TNBS treatment had less inflammation (p < 0.05) and fibrosis (p < 0.05). No differences were observed between PGE2/Indo/TNBS and PGE2/TNBS-treated animals, however, inflammation and fibrosis were significantly decreased when compared to Indo/TNBS-treated animals at 2 (p = 0.00001 and 0.009; p = 0.0001 and 0.00001 respectively) and 6 (p = 0.029 and 0.01; p = 0.021 and 0.002 respectively) weeks. In CCD-18co cells the addition of Indo significantly increased Col1 (p = 0.00005), TIMP‑1 (p = 0.02) and TGF‑β1 (p = 0.006) and decreased MMP‑1 (p = 0.04) mRNA expression compared to PMA treatment alone suggesting that Indo can increase ECM deposition. The addition of PGE2 (± Indo) reduced Col1 (p < 0.05) and increased MMP‑1 (p < 0.05) expression compared to PMA and Indo alone with no significant changes in TIMP‑1 and TGF‑β1 mRNA levels suggesting that PGE2 decreases ECM deposition.

Conclusions: The findings demonstrate that Indo induces inflammation and fibrosis in the TNBS murine model of inflammation and fibrosis, which can be overcome with the addition of PGE2. These findings were supported by the in vitro effects of PGE2 on isolated intestinal fibroblasts suggesting that PGE2 may be a potential therapy for the prevention of intestinal fibrosis.