Reference

López-Alonso et al., Sci. Transl. Med. 10, eaam7598 (2018) translational

Authors

Inés López-Alonso, Jorge Blázquez-Prieto, Laura Amado-Rodríguez, Adrián González-López, Aurora Astudillo, Manuel Sánchez, Covadonga Huidobro, Cecilia López-Martínez, Claudia C. dos Santos, Guillermo 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−/− 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.

Description

El trabajo publicado describe cómo las células pulmonares responden al estiramiento con una serie de modificaciones que aumentan la rigidez su membrana nuclear. Esta envoltura nuclear interacciona con estructura de la cromatina subyacente y desencadena cambios en la expresión génica que favorecen la muerte celular y el daño pulmonar. La relevancia de este mecanismo en humanos se demostró en muestras de pacientes sometidos a ventilación mecánica. Sin embargo, los animales knockout para gen Zmpste24, que codifica una metaloproteasa implicada en la maduración de la Lamina-A, un componente esencial de la envoltura nuclear, son resistentes al daño pulmonar por estiramiento, ya que en ellos no se activa este mecanismo, resultando en una menor tasa de muerte celular y daño del tejido. El mismo resultado se obtuvo tratando animales con inhibidores de proteasas, un fármaco capaz de interferir con este proceso de maduración de la Lamina-A.

 

 

ATS

 

REFERENCIA DEL GRUPO INVESTIGADOR

El Grupo de Investigación Traslacional en el Paciente Crítico, dirigido por el Dr Albaiceta y donde la Dra, López-Alonso trabaja como investigadora postdoctoral, desarrolla su actividad investigadora desde el año 2003, centrada en la identificación de los mecanismos moleculares responsables del daño y reparación de los tejidos, especialmente el pulmón, en los pacientes más graves. Para ello realiza estudios de investigación que incluyen desde estudios en pacientes hasta modelos experimentales y celulares de enfermedad crítica. Toda esta actividad se ha realizado mediante financiación obtenida desde el Instituto de Salud Carlos III, la Consejería de Economía y Hacienda del Principado de Asturias, el Instituto Universitario de Oncología del Principado de Asturias (IUOPA) y el recientemente creado Instituto de Investigación Sanitaria del Principado de Asturias (ISPA).

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