Abstract: Objective To investigate the effect of pirfenidone for reducing urethral stricture following urethral injury in rats and explore the possible mechanism. Methods Thirty male SD rats were randomly assigned into negative control group, positive control group and pirfenidone group (n=10). In pirfenidone and positive control groups, the rats were subjected to incision of the posterior urethral cavernous body followed by daily intraperitoneal injection of pirfenidone (100 mg/kg) and an equivalent volume of solvent, respectively. The rats in the negative control group were given intraperitoneal injections of solvent without urethral injury. At two weeks after modeling, retrograde urethrography was performed for observing urethral stricture, and the injured urethral tissues were harvested for HE staining, Masson staining, immunohistochemical staining and Western blotting for detecting the protein expressions of α-SMA and TGF-β1. The mRNA expressions of the inflammatory factors TNF-α, IL-6, and IL-1β were detected using qRT-PCR. Results The body weight of the rats in pirfenidone group was significantly decreased compared with that in the other two groups (P<0.05). Retrograde urethrography showed significant narrowing of the urethra in the positive control group but not in the pirfenidone group. HE staining of the injured urethral tissues showed obvious proliferation of urethral epithelial cells with narrow urethral cavity and increased inflammatory cells in positive control group. The pathological findings of the urethra were similar between pirfenidone group and the negative control group. Masson staining revealed obviously reduced collagen fibers and regular arrangement of the fibers in pirfenidone group as compared to the positive control group. Compared with those in the negative control group, the expressions of α-SMA and TGF-β1 were significantly increased in the positive control group, and pirfenidone treatment significantly inhibited their expressions (P<0.05 or 0.01). Pirfenidone also significantly inhibited the mRNA expressions of TNF-α, IL-6, and IL-1β in the injured urethral tissue (P<0.05 or 0.01). Conclusion Pirfenidone can prevent urethral fibrosis and stricture after urethral injury possibly by inhibiting the TGF-β1 pathway and inflammatory response.

Key words: pirfenidone; urethra stricture; fibrosis; inflammation; transforming growth factor-β1