Antifibrotic Role of Nintedanib in Tracheal Stenosis After a Tracheal Wound. (17th May 2021) - Fan, Yuhua
Abstract : Objectives/Hypothesis: Tracheal stenosis is an obstructive disease of the upper airway that commonly develops as a result of abnormal wound healing. We evaluated the anti‐inflammatory and antifibrotic properties of nintedanib on tracheal stenosis both in vitro and in vivo. Study Design: Prospective controlled animal study and in vitro comparative study of human cells. Methods: An animal model of tracheal stenosis was induced via tracheal trauma. Postsurgical rats were orally administered with nintedanib (10 or 20 mg/kg/d) or saline (negative control) for 2 weeks, and tracheal specimens were harvested after 3 weeks. Degree of stenosis, collagen deposition, fibrotic surrogate markers expression, and T‐lymphocytic infiltration were evaluated. Human fetal lung fibroblast‐1 (HFL‐1) cells were cultured to determine the effects of nintedanib on changes of cellular biological function induced by transforming growth factor‐β1 (TGF‐β1). Results: Rat tracheal stenotic tissues exhibited thickened lamina propria with irregular epithelium, characterized by significantly increased collagen deposition and elevated TGF‐β1, collagen I, α‐SMA and fibronectin expressions. Nintedanib markedly attenuated the tracheal stenotic lesions, reduced the collagen deposition and the expression of fibrotic marker proteins, and mitigated CD4+ T‐lymphocyte infiltration. Additionally, cellular proliferation and migration were decreased dose‐dependently in TGF‐β1‐stimulated HFL‐1 cells when treated with nintedanib. Furthermore, nintedanib inhibited TGF‐β1‐induced HFL‐1 differentiation and reduced the mRNA levels of the profibrotic genes. TGF‐β1‐activated phosphorylation of the TGF‐β/Smad2/3 and ERK1/2 pathways were also blocked by nintedanib. Conclusion: Nintedanib effectively prevented tracheal stenosis in rats by inhibiting fibrosis and inflammation. The antifibrotic effect of nintedanib may be achieved by inhibiting fibroblasts' proliferation, migration and differentiation and suppressing the TGF‐β1/Smad2/3 and ERK1/2 signaling pathways. Level of Evidence: NA Laryngoscope, 131:E2496–E2505, 2021