mTORC1 as a Therapeutic Target to Mitigate Development of Airway Stenosis in Response to Injury

Airway stenosis is a morbid health condition impacting the voice, breathing, and swallowing. Etiology involves endotracheal intubation or other mechanical injury, but the underlying molecular mechanisms are not fully understood. Emerging evidence suggests a role for mTOR complex 1 (mTORC1) in the pathogenesis of laryngotracheal stenosis (LTS) and that rapamycin, an mTOR inhibitor, can mitigate development of LTS. In the present study, mTORC1 was targeted genetically and pharmacologically in an injury-induced tracheal stenosis mouse model.

Human tracheal tissues were immunostained for phosphorylated ribosomal protein S6 kinase (pS6K), a downstream target of mTORC1 kinase activity, to assess mTORC1 activation. mTORC1 was genetically ablated in tracheal mesenchyme of doxycycline-inducible Rptor knockout mice (Tbx4-rtTA/Tet-On-Cre/Rptor^fl/fl) and compared to wildtype controls, both subjected to tracheal injury. On Day 21 post injury, tracheas were harvested and tracheal lamina propria thickness (LPT) was measured. Pharmacological ablation was performed with early (Day 0-7 post injury) and late (Day 8-21 post injury) systemic rapamycin treatment.

Tracheal injury increased LPT compared to sham control. This effect was eliminated by genetic ablation of mTORC1, with mutant mice having no change in LPT compared to mutant sham control and significantly lower LPT than injured wildtype littermate controls. Early rapamycin significantly reduced the expected increase in injured tracheal LPT compared to early vehicle control, while late rapamycin had no effect compared to late vehicle control.

These results indicate that mTORC1 activity within tracheal mesenchyme is required for tracheal stenosis formation following injury and is an important therapeutic target.

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