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

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 preserved alveolar nuclear membrane compliance after mechanical ventilation in mice. Ventilator-induced proapoptotic gene expression changes and lung injury were reduced in mice lacking 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 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.

Sex susceptibility to ventilator-induced lung injury

“…After 2.5 h, animals were sacrificed and the lungs removed and fixed. There were no differences in lung injury, addressed using a semiquantitative score [9] (0.5 ± 0.5 vs 0.75 ± 0.52 for female and male animals respectively at baseline, 2.3 ± 1.2 vs 2.2 ± 1.3 for female and male animals respectively after VILI, n = 6 per condition, p < 0.001 for the effect of ventilation, p = 0.99 for the effect of sex in a two-way ANOVA). Using a more aggressive ventilatory strategy (peak pressure 20 cmH 2 O, PEEP 0 cmH 2 O, respiratory rate 50 breaths/minute, inspiratory to expiratory ratio 1:1, FiO 2 0.21) yielded slightly higher scores but again without differences between sexes (2.5 ± 1.3 vs 2.7 ± 1.3 for female and male mice, n = 3 per group, p = 0.88).…”

“…p values were corrected using the Benjamini-Hochberg method. These methods have been detailed elsewhere [9]. Mechanical ventilation induced significant changes in 3510 genes, irrespective of the sex.…”

Accelerated aging induced by deficiency of Zmpste24 protects old mice to develop bleomycin-induced pulmonary fibrosis

“…Likewise, the mechanosensitive gene of early growth factor response 1 (Egr1) was also upregulated. This transcription factor was found overexpressed in mice protected from lung hyperventilation injury [32], and has an important role in the inflammatory response [33]. Accordingly, functional analysis revealed altered immune and inflammatory response.…”

Lamin A/C negatively regulated by miR‐124‐3p modulates apoptosis of vascular smooth muscle cells during cyclic stretch application in rats

“…In mechano‐responsive processes, lamin A and C are stress‐sensitive molecules that have been widely studied. For example, when BEAS‐2b cells are subjected to 18% equibiaxial stretch, the expression of lamin A and its ratio to lamin B expression both increase significantly, which then changes the compliance of nuclei …”

“…For example, when BEAS-2b cells are subjected to 18% equibiaxial stretch, the expression of lamin A and its ratio to lamin B expression both increase significantly, which then changes the compliance of nuclei. 20 Although studies have proven that different kinds of mechanical stimuli regulate lamin A/C, the detailed mechanisms involved in these processes are still unclear. Transcriptional regulation, protein synthesis, degradation and rearrangement may all participate in varying the expression of lamin A/C.…”