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

Science Translational Medicine
Inés López-AlonsoGuillermo M Albaiceta

Abstract

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 -/- anim...Continue Reading

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Citations

Jan 13, 2019·Intensive Care Medicine Experimental·Inés López-AlonsoGuillermo M Albaiceta
Nov 30, 2020·Mechanisms of Ageing and Development·Covadonga HuidobroGuillermo M Albaiceta
Jan 31, 2021·Translational Research : the Journal of Laboratory and Clinical Medicine·Jorge Blázquez-PrietoGuillermo M Albaiceta
Oct 31, 2021·Laboratory animal research·Jon Petur JoelssonSigurbergur Karason
Dec 4, 2021·Intensive Care Medicine Experimental·Paula Martín-VicenteLaura Amado-Rodríguez

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