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bioRxiv2026

Annexin A2 Regulates Surfactant Dysfunction During Injurious Ventilation.

The Acute Respiratory Distress Syndrome (ARDS) is a life-threatening cause of respiratory failure, and patients who develop ARDS frequently require mechanical ventilation, which puts them at risk of developing ventilator induced lung injury (VILI). Both VILI and ARDS can induce pulmonary surfactant dysfunction, but the mechanisms are not known. Here we report a novel role for a phospholipid binding protein, Annexin A2 (AnxA2), in the regulation of surfactant composition and function following injurious ventilation. Wild type and AnxA2-/-mice were subjected to injurious ventilation and we found that AnxA2-/- mice developed stiffer lungs following VILI that was not due to differences in barrier permeability or inflammation. Furthermore, we found that pulmonary surfactant from AnxA2-/- mice had reduced surface tension lowering properties and that this was due to a reduction in 1-palmitoyl-2-oleoylphosphatidylglycerol, or POPG. Quantitative analysis of surface tension-surface area hysteresis loops obtained from surfactant isolated from AnxA2-/- mice showed a defect in phase transitions during compression. In summary, Annexin A2 regulates surfactant function during injurious ventilation and may serve as a novel therapeutic target to prevent surfactant dysfunction in patients with ARDS who require mechanical ventilation.

molecular biology↗

bioRxiv2020

Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome

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.

molecular biology↗