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Lee H, Fei Q, Streicher A, et al. mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury. JCI Insight. 2021;6(14)doi: 10.1172/jci.insight.137708.
Lee, H., Fei, Q., Streicher, A., Zhang, W., Isabelle, C., Patel, P., Lam, H. C., Arciniegas-Rubio, A., Pinilla-Vera, M., Amador-Munoz, D. P., Barragan-Bradford, D., Higuera-Moreno, A., Putman, R. K., Sholl, L. M., Henske, E. P., Bobba, C. M., Higuita-Castro, N., Shalosky, E. M., Hite, R. D., Christman, J. W., Ghadiali, S. N., Baron, R. M., & Englert, J. A. (2021). mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury. JCI insight, 6(14), . https://doi.org/10.1172/jci.insight.137708
Lee, Hyunwook, et al. "mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury." JCI insight vol. 6,14 (2021). doi: https://doi.org/10.1172/jci.insight.137708
Lee H, Fei Q, Streicher A, Zhang W, Isabelle C, Patel P, Lam HC, Arciniegas-Rubio A, Pinilla-Vera M, Amador-Munoz DP, Barragan-Bradford D, Higuera-Moreno A, Putman RK, Sholl LM, Henske EP, Bobba CM, Higuita-Castro N, Shalosky EM, Hite RD, Christman JW, Ghadiali SN, Baron RM, Englert JA. mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury. JCI Insight. 2021 Jul 22;6(14). doi: 10.1172/jci.insight.137708. PMID: 34138757; PMCID: PMC8410036.
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JCI Insight. 2021 Jul 22;6(14). doi: 10.1172/jci.insight.137708.

mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

JCI insight

Hyunwook Lee, Qinqin Fei, Adam Streicher, Wenjuan Zhang, Colleen Isabelle, Pragi Patel, Hilaire C Lam, Antonio Arciniegas-Rubio, Miguel Pinilla-Vera, Diana P Amador-Munoz, Diana Barragan-Bradford, Angelica Higuera-Moreno, Rachel K Putman, Lynette M Sholl, Elizabeth P Henske, Christopher M Bobba, Natalia Higuita-Castro, Emily M Shalosky, R Duncan Hite, John W Christman, Samir N Ghadiali, Rebecca M Baron, Joshua A Englert

Affiliations

  1. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, and.
  2. The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State Wexner Medical Center, Columbus, Ohio, USA.
  3. Division of Pulmonary and Critical Care Medicine, Department of Medicine, and.
  4. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  5. Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, USA.
  6. Division of Pulmonary, Critical Care, and Sleep Medicine, The University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

PMID: 34138757 PMCID: PMC8410036 DOI: 10.1172/jci.insight.137708

Abstract

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.

Keywords: Pulmonary surfactants; Pulmonology; Signal transduction

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