Dexmedetomidine reduces ventilator-induced lung injury via ERK1/2 pathway activation

Mol Med Rep. 2020 Dec;22(6):5378-5384. doi: 10.3892/mmr.2020.11612. Epub 2020 Oct 19.

Abstract

Mechanical ventilation (MV) can contribute to ventilator‑induced lung injury (VILI); dexmedetomidine (Dex) treatment attenuates MV‑related pulmonary inflammation, but the mechanisms remain unclear. Therefore, the present study aimed to explore the protective effect and the possible molecular mechanisms of Dex in a VILI rodent model. Adult male Sprague‑Dawley rats were randomly assigned to one of seven groups (n=24 rats/group). Rats were euthanized after 4 h of continuous MV, and pathological changes, lung wet/dry (W/D) weight ratio, the levels of inflammatory cytokines (IL‑1β, TNF‑α and IL‑6) in the bronchoalveolar lavage fluid (BALF), and the expression levels of Bcl‑2 homologous antagonist/killer (Bak), Bcl‑2, pro‑caspase‑3, cleaved caspase‑3 and the phosphorylation of ERK1/2 in the lung tissues were measured. Propidium iodide uptake and TUNEL staining were used to detect epithelial cell death. The Dex pretreatment group exhibited fewer pathological changes, lower W/D ratios and lower expression levels of inflammatory cytokines in BALF compared with the VILI group. Dex significantly attenuated the ratio of Bak/Bcl‑2, cleaved caspase‑3 expression levels and epithelial cell death, and increased the expression of phosphorylated ERK1/2. The protective effects of Dex could be partially reversed by PD98059, which is a mitogen‑activated protein kinase (upstream of ERK1/2) inhibitor. Overall, dexmedetomidine was found to reduce the inflammatory response and epithelial cell death caused by VILI, via the activation of the ERK1/2 signaling pathway.

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Cytokines / metabolism
  • Dexmedetomidine / metabolism
  • Dexmedetomidine / pharmacology*
  • Disease Models, Animal
  • Lung / pathology
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism
  • Pneumonia / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Ventilator-Induced Lung Injury / drug therapy*
  • Ventilator-Induced Lung Injury / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism

Substances

  • Bak1 protein, rat
  • Cytokines
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • bcl-2 Homologous Antagonist-Killer Protein
  • Dexmedetomidine
  • Mitogen-Activated Protein Kinases