TY - JOUR
T1 - mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury
AU - Lee, Hyunwook
AU - Fei, Qinqin
AU - Streicher, Adam
AU - Zhang, Wenjuan
AU - Isabelle, Colleen
AU - Patel, Pragi
AU - Lam, Hilaire C.
AU - Arciniegas-Rubio, Antonio
AU - Pinilla-Vera, Miguel
AU - Amador-Munoz, Diana P.
AU - Barragan-Bradford, Diana
AU - Higuera-Moreno, Angelica
AU - Putman, Rachel K.
AU - Sholl, Lynette M.
AU - Henske, Elizabeth P.
AU - Bobba, Christopher M.
AU - Higuita-Castro, Natalia
AU - Shalosky, Emily M.
AU - Duncan Hite, R.
AU - Christman, John W.
AU - Ghadiali, Samir N.
AU - Baron, Rebecca M.
AU - Englert, Joshua A.
N1 - Funding Information:
This work was partially supported by NIH Grants K08 GM102695 (to JAE), R56 HL142767 (to JAE, SNG, and RDH), R01HL142767 (to JAE and SNG), R01 HL142093 (to RMB), and an Ohio State University Presidential Fellowship (to CMB). This work was also supported by vouchers from The Ohio State Center for Clinical and Translational Science (UL1TR002733). We would like to thank The Ohio State University Comparative Pathology and Mouse Phenotyping Core and Sue Knoblaugh for their assistance in preparing and staining and in interpreting histologic sections, The Ohio State University College of Medicine Medical Scientist Training Program, and the Davis Heart and Lung Research Institute at The Ohio State University.
Publisher Copyright:
Copyright: © 2021, Lee et al.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. 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 impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.
AB - The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. 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 impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.
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U2 - 10.1172/jci.insight.137708
DO - 10.1172/jci.insight.137708
M3 - Article
C2 - 34138757
AN - SCOPUS:85111052494
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 14
M1 - e137708
ER -
