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Sci Transl Med. 2018 Aug 29;10(456). pii: eaam7598. doi: 10.1126/scitranslmed.aam7598.

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

Author information

1
Área del Corazón, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
2
Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33005 Oviedo, Spain.
3
Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain.
4
Centro de Investigación Biomédica En Red-Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain.
5
Department of Anesthesiology and Operative Intensive Care Medicine, Charité Universitätsmedizin, 10117 Berlin, Germany.
6
Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
7
Departamento de Cirugía y Especialidades Médicoquirúrgicas, Universidad de Oviedo, 33005 Oviedo, Spain.
8
Área de Farmacología, Departamento de Medicina, Universidad de Oviedo, 33005 Oviedo, Spain.
9
Interdepartmental Division of Critical Care, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario M5B 1WB, Canada.
10
Área del Corazón, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain. guillermo.muniz@sespa.es.

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-/- 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.

PMID:
30158154
DOI:
10.1126/scitranslmed.aam7598
[Indexed for MEDLINE]

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