Preventing loss of mechanosensation by the nuclear membranes of alveolar cells reduces lung injury in mice during mechanical ventilation

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Science Translational Medicine  29 Aug 2018:
Vol. 10, Issue 456, eaam7598
DOI: 10.1126/scitranslmed.aam7598

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Softening the effects of lung ventilation

Mechanical ventilation is a life support treatment that helps patients to breathe; however, the mechanical stress caused by artificial pressure can cause lung injury. The molecular mechanisms responsible for this adverse event are not completely understood. Now, López-Alonso et al. show that Lamin-A overexpression induced by mechanical ventilation increased nuclear membrane stiffness (that is, reduced compliance) in lung alveolar cells and contributed to lung injury in mice. Inhibition of nuclear Lamin-A production using two protease inhibitors approved for treating human immunodeficiency virus infection preserved alveolar nuclear membrane compliance and reduced lung injury induced by mechanical ventilation. The results suggest that protease inhibitors might be useful for reducing the side effects associated with mechanical ventilation.


The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may result in clinically relevant alveolar damage. We report that mechanical ventilation in mice increased the expression of Lamin-A, a major determinant of nuclear membrane stiffness, in alveolar epithelial cells. Lamin-A expression increased and nuclear membrane compliance decreased in human bronchial epithelial cells after a mechanical stretch stimulus and in a murine model of lung injury after positive-pressure ventilation. Reducing Lamin-A maturation by depletion of the protease-encoding gene Zmpste24 preserved alveolar nuclear membrane compliance after mechanical ventilation in mice. Ventilator-induced proapoptotic gene expression changes and lung injury were reduced in mice lacking Zmpste24 compared to wild-type control animals. Similarly, treatment with the human immunodeficiency virus protease inhibitors lopinavir and ritonavir reduced the accumulation of Lamin-A at nuclear membranes and preserved nuclear membrane compliance after mechanical ventilation, mimicking the protective phenotype of Zmpste24−/− animals. These results show that the pathophysiological response to lung mechanical stretch is sensed by the nuclear membranes of lung alveolar cells, and suggest that protease inhibitors might be effective in preventing ventilator-induced lung injury.

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