Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome
| Autor: | Colleen Isabelle, Angelica Higuera, Rebecca M. Baron, R. Duncan Hite, Hilaire C. Lam, Hyunwook Lee, Wenjuan Zhang, Joshua A. Englert, Adam Streicher, Rachel K. Putman, Qinqin Fei, John W. Christman, Natalia Higuita-Castro, Samir N. Ghadiali, Christopher M Bobba, Pragi Patel, Diana Barragan-Bradford, Elizabeth P. Henske, Miguel Pinilla-Vera, Diana Amador-Munoz |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Mechanical ventilation
0303 health sciences ARDS Lung business.industry medicine.medical_treatment Inflammation mTORC1 Lung injury respiratory system medicine.disease respiratory tract diseases 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure 030228 respiratory system Respiratory failure Cancer research medicine Mechanosensitive channels medicine.symptom biological phenomena cell phenomena and immunity business 030304 developmental biology |
| DOI: | 10.1101/2020.03.02.973081 |
| Popis: | Acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation maintains gas exchange in patients with ARDS, but exposes lung cells to physical forces that exacerbate lung injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during mechanical ventilation exacerbates lung injury. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells exacerbates physiologic lung dysfunction during mechanical ventilation. Conversely, treatment with rapamycin at the time mechanical ventilation is initiated prevents physiologic lung injury (i.e. decreased compliance) without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during mechanical ventilation. Our data demonstrate that in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during mechanical ventilation exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator induced lung injury during ARDS. |
| Databáze: | OpenAIRE |
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