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MTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

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.

SUBMITTER: Lee H

PROVIDER: S-EPMC8410036 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH2O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH2O.

Project description:BackgroundInvasive mechanical ventilation (IMV) has become one of the mainstays of therapy in NICUs worldwide, as a result of which premature babies with extremely low birth weight have been able to survive. Although lifesaving, IMV can result in lung inflammation and injury. Surfactant therapy is considered a standard of care in preterm infants with immature lungs. Recently, small molecule inhibitors like siRNAs and miRNAs have been used for therapeutic purposes. Ddit3 (CHOP), Ang2 and miR34a are known to be upregulated in experimental lung injury. We wanted to test whether inhibitors for these molecules (CHOP siRNA, Ang2 siRNA, and miR34a antagomir) if used alone or with a combination with surfactant (Curosurf®) would help in reducing ventilation and hyperoxia-induced injury in an experimental lung injury model.MethodsPreterm rabbits born by cesarean section were intratracheally instilled with the three small molecule inhibitors with or without Curosurf® prior to IMV and hyperoxia exposure. Prior to testing the inhibitors in rabbits, these small molecule inhibitors were transfected in mouse lung epithelial cells (MLE12 and AECII) and delivered to neonatal mouse pups intranasally as a proof of concept that surfactant (Curosurf®) could be used as an effective vehicle for administration of such drugs. Survival, pulmonary function tests, histopathology, immunostaining, quantitative PCR and western blotting were done to see the adjuvant effect of surfactant with these three small molecule inhibitors.ResultsOur data shows that Curosurf® can facilitate transfection of small molecules in MLE12 cells with the same and/or increased efficiency as Lipofectamine. Surfactant given alone or as an adjuvant with small molecule inhibitors increases survival, decreases IMV and hyperoxia-induced inflammation, improves pulmonary function and lung injury scores in preterm rabbit kits.ConclusionOur study shows that Curosurf® can be used successfully as an adjuvant therapy with small molecule inhibitors for CHOP/Ang2/miR34a. In this study, of the three inhibitors used, miR34a inhibitor seemed to be the most promising compound to combat IMV and hyperoxia-induced lung injury in preterm rabbits.

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MTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

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