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* = Presenting author

P003 Anti-fibrotic Effects of Pirfenidone in Gut-derived Fibroblasts from Patients with Active Crohn's Disease

S.-I. Kadir*1, T.W. Kragstrup2, A. Dige1, S. Jensen2, J.F. Dahlerup1, J. Kelsen3

1Aarhus University Hospital, Department of Hepatology and Gastroenterology, Aarhus, Denmark, 2Aarhus University, Institute of Biomedicine, Department of Immunology, Aarhus, Denmark, 3Regional Hospital Randers, Medical Department, Randers, Denmark

Background

Crohn's disease (CD) patients suffering from complications of intestinal fibrosis and stricture formation often require repeated surgical resection. However, the high recurrence rate associated with resection necessitates the exploration of new therapeutic approaches. Pirfenidone (Esbriet®, Pirespa®) (PFD), an anti-fibrotic and anti-inflammatory drug approved in Europe for the treatment of idiopathic pulmonary fibrosis, may be able to inhibit the proliferation and matrix formation of gut-derived fibroblasts from CD patients and may be a candidate drug for prevention of stricture formation in CD.

Methods

Fibroblasts were isolated from endoscopic biopsies from macroscopically inflamed (n=8) and non-inflamed (n=5) colonic mucosa or from surgical specimens from strictured ileal mucosa (n=2). As a control fibroblast population we used a fibroblast cell line derived from human neonatal foreskin (strain BJ; ATCC no. CRL-2522). The fibroblasts were cultured with increasing concentrations of PFD and we studied the impact on fibroblast proliferation, collagen synthesis and production of MMP-3 and TIMP-1.

Results

PFD inhibited the proliferation of gut-derived fibroblasts in a dose-dependent way (Figure 1.A) (P<0.0001). PFD was added in the following concentrations: 0.5 mg/ml, 1.0 mg/ml, and 2.0 mg/ml. The relative inhibitory effect of PFD was 0.93 (IQR 0.91-0.98); 0.77 (IQR 0.72-0.86); and 0.58 (IQR 0.49-0.63) respectively. Importantly, the inhibitory effect of PFD on fibroblast proliferation was reversible in vitro (Figure 1.B).

 

ECCOJC jju027 P003 F0001

“Figure 1: Suppression of fibroblast proliferation. A) The fibroblast proliferation decreased after treatment with PFD dose-dependently. B) The suppression was reversible for all conc. of PFD.”

PFD, in the same amounts as above, significantly inhibited collagen synthesis and the production of both MMP-3 and TIMP-1 dose-dependently (all P<0.0001). For MMP-3 the median relative inhibition was 0.81 (IQR 0.67–0.94); 0.71 (IQR 0.61–0.83); and 0.62 (IQR 0.52–0.67) respectively (Figure 2.A). For TIMP-1 the median relative inhibitory effect was 1.11 (IQR 0.92-0.1.20); 0.97 (IQR 0.87–1.16); and 0.72 (IQR 0.61–0.82) respectively (Figure 2.B).

 

ECCOJC jju027 P003 F0002

“Figure 2: Suppression of fibroblast production of MMP-3 and TIMP-1. Fibroblast production of A) MMP-3 and B) TIMP-1 decreased after treatment with pirfenidone in a dose-dependent manner.”

 

 

Conclusion

PFD inhibits the proliferation and secretion of collagen, MMP-3 and TIMP-1 in fibroblasts from CD patients. Our observations of the impact of PFD on fibroblast proliferation support the use of PFD in the treatment of stricturing CD.