Cellular senescence limits acute lung injury induced by mechanical ventilation

Different forms of lung injury can activate senescence pathways. Senescence has been involved in chronic lung diseases, but its role in the acute phase is less known. Acute lung injury activates a large variety of pathogenetic mechanisms that can lead to respiratory insufficiency. In some cases, mechanical ventilation may help to maintain gas exchange, but positive airway pressures can cause regional overdistension of alveolar units and further damage. Here, we report that acute lung injury and alveolar overstretching activate a lung senescent program aimed to limit apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of a specific senescence signature. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed the activation of the Tp53/Cdkn1a (p21) senescence pathway, increases in senescence-associated heterochromatin foci in alveolar cells and markers of DNA damage, chromatin reorganization and changes in the nuclear envelope. Autopsy samples from lungs of critically ill patients showed the increase in senescence-associated heterochromatin foci. Cell stretch per se was also able to activate the senescence response in an ex-vivo model. Absence of Cdkn1a decreased the senescent response, but worsened lung injury by a significant increase in apoptosis. In opposite, treatment with lopinavir/ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. Collectively, these results suggest that acute injury promotes lung senescence. This response plays a protective role against acute lung injury in the short term, but its long-term consequences remain unexplored.