EW-7197, a Transforming Growth Factor-Beta Type I Receptor Kinase Inhibitor, Ameliorates Acquired Lymphedema in a Mouse Tail Model

Background: Acquired lymphedema is a common consequence of cancer surgery. Fibrosis is one of the main causes of chronic lymphedema since it hinders lymphatic regeneration and this causes a significant decrease in lymphatic flow and accumulation of excessive protein-rich fluid. The transforming growth factor-beta 1 (TGF-beta 1) signaling pathway is known in a process of wound repair and fibrosis. In our study, the purpose was to evaluate the efficacy of EW-7197, a peroral TGF-beta type I receptor kinase inhibitor, in treating acquired lymphedema. Methods and Results: For lymphedema mouse tail model, we used 10- to 12-week-old female C57BL/6 mice. The skin was circumferentially excised, making a circular band followed by cauterization of lymphatic collecting vessels. Two groups were made in this study: control and treatment. The treatment group (n = 12) received a solution consisting of 0.1 mL of artificial gastric juice and 20 mg/kg EW-7197 by gavage once daily. For evaluation, tail diameter measurement, fluorescence lymphography, and immunofluorescence images were used. EW-7197 treatment ameliorates acquired lymphedema in a mouse tail model by increasing lymphangiogenesis and interstitial flow of the lymphatics by inhibition of the fibrosis. The differences in maximal tail thicknesses between the control and treatment groups were statistically significant from 2 to 4 weeks after surgery. The treatment group showed a greater number of lymphatic vessels at the surgery site than the control group. The treatment group also showed more FITC coverage area at the surgery site. Conclusion: EW-7197 treatment ameliorates acquired lymphedema in a mouse tail model by increasing lymphangiogenesis and interstitial flow.