Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation

Nat Commun. 2021 Jan 12;12(1):289. doi: 10.1038/s41467-020-20449-w.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Bronchoalveolar Lavage
  • Female
  • Gene Transfer Techniques*
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology
  • Interleukin-8 / metabolism
  • Lung Injury / genetics*
  • Macrophages, Alveolar / metabolism*
  • Male
  • Mechanotransduction, Cellular*
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Middle Aged
  • Nanoparticles / chemistry*
  • Respiration, Artificial / adverse effects*
  • THP-1 Cells
  • Up-Regulation / genetics

Substances

  • Interleukin-8
  • MIRN146 microRNA, human
  • MicroRNAs