EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus

Abstract

Self-expanding metallic stent (SEMS) placement is a well-established method for treating malignant esophageal strictures; however, this procedure has not gained widespread acceptance for treating benign esophageal strictures because of granulation tissue formation. The aim of the present study was to investigate whether EW-7197, a novel per-oral transforming growth factor-β type I receptor kinase inhibitor, suppressed granulation tissue formation after SEMS placement in the rat esophagus. Sixty rats underwent SEMS placement and were randomly divided into 4 groups. Group A (n= 20) received vehicle-treated control for 4 weeks. Group B (n= 20) received 20 mg/kg/day EW-7197 for 4 weeks. Group C (n= 10) received 20 mg/kg/day EW-7197 for 4 weeks followed by vehicle-treated control for 4 weeks. Group D (n= 10) received 20 mg/kg/day EW-7197 for 8 weeks. SEMS placement was technically successful in all rats. Eleven rats, however, were excluded because of stent migration (n= 9) and procedure-related death (n= 2). The luminal diameter in group A was significantly smaller than those in groups B, C, and D (all P< .001). The percentage of granulation tissue area, number of epithelial layers, thickness of submucosal fibrosis, percentage of connective tissue area, and degree of collagen deposition were significantly higher in group A than in groups B, C, and D (all P< .001); however, there were no significant differences among groups B, C, and D. EW-7197 decreased the expression levels of phospho-Smad 3, N-cadherin, fibronectin, α-smooth muscle actin, and transforming growth factor-β1 and increased the expression level of E-cadherin (all P< .01). EW-7197 suppressed granulation tissue formation after SEMS placement in the rat esophagus.