Knockdown of SOX9 alleviates tracheal fibrosis through the Wnt/β-catenin signaling pathway.

Abstract

Trachealfibrosis is an important cause of tracheal stenosis without effective treatments, and new drug targets need to be developed. The role of SOX9 in the injury and repair of the trachea is unknown; this study aims to investigate the role of SOX9 in the regulation of tracheal fibrosis based on clinical samples from patients with tracheal injury and a model of tracheal fibrosis produced by tracheal brushing in rats. The results showed that the expressions of SOX9 and mesenchymal and ECM-related indicators were increased in the injury and fibrosis of the trachea in patients and rats. Serum SOX9 levels exhibited a sensitivity of 83.87% and specificity of 90% in distinguishing patients with tracheal fibrosis from healthy volunteers when the cut‑off value was 13.24ng/ml. Knockdown SOX9 can markedly inhibit granulation tissue proliferation, reduce inflammation and ECM deposition, promote epithelial regeneration and granulation tissue apoptosis, and attenuate the tracheal fibrosis after injury. Additionally, RNA sequencing showed that the proliferation, migration, and ECM deposition of tracheal granulation tissue were related to the activation of Wnt pathway, activation of the β-catenin, and p-GSK3β after injury can be inhibited by the knockdown of SOX9. In summary, SOX9 is upregulated in tracheas fibrosis and may be a novel factor to promote tracheal fibrosis progression. Inhibiting SOX9 may be used to prevent and treat tracheal fibrosis in the future. KEY MESSAGE : The expression of SOX9 is upregulated the process of injury and repair of the tracheal fibrosis. Knocking down SOX9 can attenuate tracheal fibrosis after injury by inhibiting inflammation response, granulation tissue proliferation, ECM deposition, and promoting granulation tissue apoptosis. The Wnt/β-catenin-SOX9 axis is activated during tracheal injury and fibrosis, and inhibition of SOX9 can partially alleviate tracheal fibrosis. SOX9 may act as a new diagnostic and therapeutic target in patients with tracheal fibrosis in the future.