Cellular senescence limits acute lung injury induced by mechanical ventilation

Jorge Blazquez-Prieto; Covadonga Huidobro; Ines Lopez-Alonso; Laura Amado-Rodriguez; Paula Martin-Vicente; Cecilia Lopez-Martinez; Irene Crespo; Cristina Pantoja; Pablo J Fernandez-Marcos; Manuel Serrano; Jacob I Sznajder; Guillermo M Albaiceta

Mechanical overstretch appears to be an important pathogenic factor in these settings. Contrasting with cell models, previous studies have shown the need of two different hits to trigger both lung senescence and repair in animal models (27) . In our work, the combination of acid instillation and mechanical ventilation was required to observe senescence-associated heterochromatin foci. In smooth muscle cells, stretch leads to p53 activation and upregulation of senescence markers (28), resembling our findings in A549 cells. Several mechanisms have linked the mechanical load to this biological response, including oxidative stress and MAPK activation (29) . Our work focused on the role of the nuclear envelope as a critical structure regulating both mechanosensing and senescence. The mechanical load is transmitted from the extracellular matrix to the cytoskeleton and then to the nuclear membrane (30) . This causes a change in the nuclear lamina, reorganization of the underlying chromatin and DNA damage (31) . On the other hand, abnormalities of this nuclear lamina activate a pro-senescent program in the cell (9, 32) . Several HIV protease inhibitors, such as lopinavir/ritonavir, inhibit ZMPSTE-24, a protease responsible for Lamin-A maturation (19), thus preserving nuclear compliance and decreasing stretch induced apoptosis and VILI (8) . The findings . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.24.005983 doi: bioRxiv preprint reported here suggest that these benefits are due to an increased senescent response.