Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1

Am J Physiol Cell Physiol. 2018 Apr 1;314(4):C449-C455. doi: 10.1152/ajpcell.00173.2017. Epub 2018 Jan 10.

Abstract

MicroRNA-199a (miR-199a) is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could upregulate miR-199a in alveolar macrophages. Downregulation of miR-199a inhibited the upregulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of proinflammatory cytokines, and the upregulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a. We further identified sirtuin 1 (SIRT1) as a direct target of miR-199a in alveolar macrophages, and the expression of SIRT1 was negatively correlated with the level of miR-199a. The protective role of miR-199a downregulation in LPS-stimulated alveolar macrophages and sepsis-induced ARDS could be attenuated by SIRT1 inhibitor. Taken together, these results indicate that downregulation of miR-199a might protect lung tissue against sepsis-induced ARDS by upregulation of SIRT1 through the suppression of excessive inflammatory responses and the inhibition of cellular apoptosis in lung tissue, suggesting its potential therapeutic effects on sepsis-induced ARDS.

Keywords: ARDS; SIRT1; macrophage; microRNA-199a; sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Acute Lung Injury / enzymology
  • Acute Lung Injury / genetics
  • Acute Lung Injury / microbiology
  • Acute Lung Injury / prevention & control*
  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism*
  • Apoptosis / drug effects
  • Binding Sites
  • Burns / microbiology
  • Carbazoles / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Gene Expression Regulation, Enzymologic
  • Histone Deacetylase Inhibitors / pharmacology*
  • Inflammation Mediators / metabolism
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / microbiology
  • Lung / pathology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / enzymology
  • Macrophages, Alveolar / microbiology
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Pseudomonas Infections / enzymology
  • Pseudomonas Infections / genetics
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / pathogenicity
  • Respiratory Distress Syndrome / enzymology
  • Respiratory Distress Syndrome / genetics
  • Respiratory Distress Syndrome / microbiology
  • Respiratory Distress Syndrome / prevention & control*
  • Sepsis / drug therapy*
  • Sepsis / enzymology
  • Sepsis / genetics
  • Sepsis / microbiology
  • Signal Transduction / drug effects
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*

Substances

  • 3' Untranslated Regions
  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
  • Antagomirs
  • Carbazoles
  • Cytokines
  • Histone Deacetylase Inhibitors
  • Inflammation Mediators
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1