@article {Bobba796557, author = {Christopher Bobba and Qinqin Fei and Vasudha Shukla and Hyunwook Lee and Pragi Patel and Rachel K Putman and Carleen Spitzer and MuChun Tsai and Mark D. Wewers and John W. Christman and Megan N. Ballinger and Samir Ghadiali and Joshua A. Englert}, title = {Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates lung injury during mechanical ventilation}, elocation-id = {796557}, year = {2019}, doi = {10.1101/796557}, publisher = {Cold Spring Harbor Laboratory}, abstract = {During mechanical ventilation, injurious biophysical forces exacerbate lung injury. These forces disrupt alveolar capillary barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides such as 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 used humanized in-vitro systems, mouse models, and biospecimens from mechanically ventilated patients to elucidate the expression dynamics of miR-146a that might be required to decrease lung injury during mechanical ventilation. We found that the endogenous increase in miR-146a following injurious was relatively modest and not sufficient to prevent lung injury. However, when miR-146a was highly overexpressed using a nanoparticle-based delivery platform in vivo, it was sufficient to prevent lung injury. These data indicate that the endogenous increase in microRNA-146a during MV is a compensatory response that only partially limits VILI and that nanoparticle delivery approaches that significantly over-express microRNA-146a in AMs is an effective strategy for mitigating VILI.}, URL = {https://www.biorxiv.org/content/early/2019/10/11/796557}, eprint = {https://www.biorxiv.org/content/early/2019/10/11/796557.full.pdf}, journal = {bioRxiv} }