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).

 Descargar el artículo 

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

The Helicase PIF1 Facilitates Resection overSequences Prone to Forming G4 Structures

02-11-2018

DNA breaks are complex lesions that can be repaired either by non-homologous end joining (NHEJ) or by homologous recombination (HR). The decision between these two routes of DNA repair is...

Read more

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

01-10-2018

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...

Read more

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

03-09-2018

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear...

Read more

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

01-08-2018

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of...

Read more

A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

02-07-2018

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering...

Read more

Deciphering the Dynamic Transcriptional and Post-transcriptional Networks of Macrophages in the Healthy Heart and after Myocardial Injury

01-06-2018

Our group is interested in the behavior and transcriptional regulation of macrophages in the context of complex disease environments. We have generated a whole transcriptome dataset (mRNA, miRNA, and lincRNA)...

Read more

Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth

01-05-2018

La formación de nuevas neuritas es un proceso clave para el correcto desarrollo del sistema nervioso. El crecimiento neurítico requiere la generación de nuevas membranas. No obstante, los cambios metabólicos...

Read more

Mechanisms of bacterial membrane permeabilization by crotalicidin (Ctn) and its fragment Ctn(15-34), antimicrobial peptides from rattlesnake venom.

04-04-2018

La crotalicidina, un péptido del veneno de una serpiente de cascabel, tiene entre otras propiedades una potente acción antimicrobiana. Un fragmento resultante de la disección racional del péptido nativo presenta...

Read more

Functional optimization of broadly neutralizing HIV-1 antibody 10E8 by promoting membrane interactions

01-03-2018

El anticuerpo 10E8 representa uno de los anticuerpos anti-VIH con mayor cobertura de neutralización y potencia descrito a día de hoy. Su epítopo se localiza en una región próxima a...

Read more

Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL

01-02-2018

La legionelosis o enfermedad del legionario es una neumonía potencialmente fatal, causada por la bacteria Legionella pneumophila. Durante la infección, la bacteria trasloca un gran número de proteínas, llamadas efectores...

Read more

Protector Members