Impact of aging on pulmonary cellular responses during mechanical ventilation
Acute respiratory distress syndrome (ARDS) results in significant morbidity and mortality, especially in the elderly. Mechanical ventilation, a common supportive treatment for ARDS, is necessary for maintaining gas exchange, but can also propagate injury. We hypothesized that aging would exacerbate the pathophysiological responses to mechanical ventilation. Young and aged male mice were mechanically ventilated and changes in surfactant function, inflammation, and vascular permeability were assessed. Additionally, single-cell RNA sequencing was used to delineate cell-specific transcriptional changes. The results showed that surfactant dysfunction was augmented in aged mice, while inflammation was less pronounced in aged animals. Futhermore, vascular permeability was significantly increased with aging. Differential gene expression and pathway analyses revealed that aged endothelial cells exhibited altered cell-cell junction formation and that alveolar macrophages in aged mice showed a blunted inflammatory response. These results highlight the complex interplay between aging and mechanical ventilation, including an age-related predisposition to endothelial barrier dysfunction due to altered cell-cell junction formation and decreased inflammation, potentially due to immune exhaustion.  It is concluded that age-related vascular changes may underlie the increased susceptibility to injury during mechanical ventilation in elderly patients. Overall design: mRNA profiles of lung tissue cells from young (2-3 month old) and aged (22 month old) mice exposed to mechanical ventilation for 3 hours (3 animals were used per group and were pooled together). mRNA profiles were generated by single cell sequencing using the Illumina NextSeq 500 sequencer