Abstract
BACKGROUND: Traumatic tracheal stenosis is characterized by airway granular proliferation after trauma, which may lead to asphyxy. Abnormal activation of the ADAM17/TGF-β1 pathway may trigger excessive repair and airway fibrosis. TAPI-1 is an effective inhibitor of ADAM17, which blocks the "extracellular cleavage release" of inflammatory factors (such as TNF-α) and proliferation signals (such as EGFR ligand TGF-α) by specifically inhibiting ADAM17 (tumor necrosis factor converting enzyme). Silicone stents are considered an important method for the treatment of airway stenosis. This study aimed to investigate the role and potential mechanism of TAPI-1 combined with silicone stents in alleviating severe tracheal stenosis after trauma. METHODS: Tracheal epithelial cells were stimulated with GM-CSF and then treated after 24 h by lentivirus-mediated ADAM17 RNAi and mitomycin C. A model of severe traumatic tracheal stenosis was established in Beagle dogs. Mitomycin C, TAPI-1, and TAPI-1 combined with a silicone stent were applied to treat tracheal stenosis in the animals. The changes in the trachea were directly observed using bronchoscopy. The viability and proliferation of epithelial cells were measured using CCK-8 assay. The mRNA and protein expressions of ADAM17, TGF-β1, and fibronectin 1 were detected by qRT-PCR and western blotting. The pathological changes in traumatic tracheal stenosis were analyzed by hematoxylin and eosin staining. RESULTS: Lentivirus-mediated ADAM17 RNAi significantly inhibited the proliferation of tracheal epithelial cells induced by GM-CSF and suppressed the ADAM17/TGF-β1 signaling pathway in vitro. Moreover, TAPI-1 combined with silicone stents significantly alleviated traumatic tracheal stenosis in Beagle dogs, and TAPI-1 markedly inhibited the ADAM17/TGF-β1 signaling pathway in vivo. In conclusion, it was showed that TAPI-1 combined with silicone stents can significantly alleviate severe traumatic tracheal stenosis in Beagle dogs by inhibiting the ADAM17/TGF-β1 signaling pathway and expanding the narrowed trachea. CONCLUSIONS: TAPI-1 combined with silicone stents can be considered as a novel therapeutic approach for treating severe tracheal stenosis after trauma.