Introduction: Acquired airway stenosis forms in response to intubation or other mechanical injury but the underlying molecular mechanisms are not fully understood. mTor complex 1 (mTORC1) is a ubiquitous protein complex which regulates protein translation and thereby cellular and tissue growth in response to metabolic factors including nutrients, energy, mechanical stimuli and oxidative stress. mTORC1 mediates the development of lung injury in response to mechanical ventilation in patients with ARDS. Abnormal activation of mTORC1, is also detected in tracheal tissues from stenosis patients compared with non-intubated control patients. In the present study, the role of mTORC1 in stenosis formation is examined in an established mouse model of tracheal stenosis.
Methods: mTORC1 was genetically ablated in tracheal mesenchyme using doxycycline-inducible Rptor knockout mice (Tbx4-rtTA, tetOn Cre, Rptor -/-) and compared with wildtype littermate controls. Mice were subjected to tracheal chemomechanical injury with bleomycin coated steel brush. At 21 days post injury, mutant and wildtype tracheas were analyzed by micro CT scanning and histology. The impact of early (day 0-7 post injury) and late (day 8-21 post injugy) administration of systemic rapamycin on stenosis formation was also examined in wildtype mice.
Results: Genetic or pharmacological disruption of mTORC1 impacts the degree of tracheal stenosis formation observed in a mouse model.
Conclusion: mTORC1 is a mediator of tracheal stenosis formation and potential therapeutic target.