EW-7197, an ALK5 Inhibitor, Prevents Granulation Tissue Formation after Bare Metallic Stent Placement in a Rat Urethral Model

To evaluate the efficacy, safety, and optimal dose of EW-7197, an activin receptor-like kinase 5 (ALK-5) inhibitor, in prevention of granulation tissue formation following bare metallic stent placement using a rat urethral model. Twenty-four rats were divided into four groups and underwent fluoroscopic bare metallic stent placement in the urethra. Group A rats were treated with 0.3 mL of saline once daily for 8 weeks after stent placement. Group B, C, and D rats were treated with EW-7197 phosphate (5, 10, and 20 mg/kg, respectively) once daily for 8 weeks after stent placement. All rats were sacrificed 8 weeks after stent placement. The inner luminal diameter of the stent urethra, number of epithelial layers, thickness of submucosal fibrosis, degree of submucosal inflammatory cell infiltration, and granulation tissue-related percentage of urethral cross-sectional area stenosis, and level biologically active TGF-β were evaluated in all rats. Differences between groups were tested by using the Mann-Whitney U test. The average inner luminal diameter of the stented urethra in group C and D were significantly higher than group A at 8 weeks after stent placement (P = 0.002 and P < 0.001, respectively). The average number of epithelial layers in group A was significantly higher than group C (P < 0.001) and D (P < 0.001). The average thickness of submucosal fibrosis in group A was significantly higher than group B (P < 0.001), C (P < 0.001), and D (P < 0.001). The average degree of inflammatory cell infiltration in group A was significantly lower than group B (P = 0.048), C (P = 0.003), and D (P = 0.001). The average percentage of granulation tissue areas in group A was significantly higher than group C (P = 0.003) and D (P = 0.011). The RT-PCR product of TGF-β in group B, C, and D was significantly lower than group A (P = 0.130, P < 0.001, and P = 0.001, respectively). EW-7197 at a dose of 10 and 20 mg/kg were effective and safe for the prevention of granulation tissue hyperplasia after bare metallic stent placement a rat urethral model.