Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation. There are no targeted pharmacologic therapies to treat lung injury during mechanical ventilation (MV). Here the authors identify a mechanosensitive microRNA (miR-146a) in alveolar macrophages during MV and increase miR-146a to supraphysiological levels in these cells to mitigate ventilator induced lung injury.
【저자키워드】 Respiratory tract diseases, Non-coding RNAs, 【초록키워드】 therapy, mechanical ventilation, microRNA, Ventilation, lung, Lung injury, proinflammatory, Patient, Mouse models, expression, MicroRNAs, platform, alveolar macrophage, regulate, Injury, In-vitro, ventilator, therapeutic potential, treat, oligonucleotide, mitigate, humanized, Prevent, effective, limit, decrease, identify, generate, increase in, overexpressed, these cell, disrupt, exacerbate, biospecimen, Mechanical, 【제목키워드】 Macrophage, mechanical ventilation, lung, nanoparticle, regulate, Injury, mitigate,