Abstract
There is a growing contradiction between the rising demand for mechanical ventilation among the elderly and their heightened sensitivity to ventilator-induced lung injury (VILI). This discrepancy compels us to explore therapeutic targets for VILI in elderly patients. Our research revealed that aging increases the sensitivity of pulmonary endothelial cells to low-magnitude mechanical stretch. By analyzing transcriptome sequencing data from lung tissues of humans and mice at different ages, as well as published transcriptome sequencing data from senescent endothelial cells, we identified tissue kallikrein-related peptidase 8 (KLK8) as an age-dependent upregulated gene in lung tissues. Using KLK8 knockout mice, intra-pulmonary KLK8-overexpressing mice, and mouse lung vascular endothelial cells (MLVECs) with KLK8 overexpression or knockdown, we demonstrated that age-dependent KLK8 upregulation contributes to pulmonary endothelial senescence and increased susceptibility of aged mice to VILI. Mechanistically, KLK8 promotes pulmonary endothelial senescence by inactivating the fibronectin/focal adhesion kinase (FAK) pathway. Through transcriptional profiling, we identified the poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor olaparib as a potential agent that rescues KLK8-induced pulmonary endothelial cell senescence and alleviates VILI in aged mice. Our findings underscore the critical role of KLK8 in pulmonary endothelial senescence and provide preclinical evidence for PARP1/2 inhibitors as a therapeutic target for VILI in elderly individuals.