Sivelestat improves acute lung injury by inhibiting PI3K/AKT/mTOR signaling pathway

PLoS One. 2024 Jun 27;19(6):e0302721. doi: 10.1371/journal.pone.0302721. eCollection 2024.

Abstract

Objective: To investigate the therapeutic effect and mechanism of sivelestat sodium on acute lung injury (AIL).

Methods: A rat model for ALI/acute respiratory distress syndrome (ALI/ARDS) was established. Pathological examination of lung tissue was conducted to assess lung injury. Blood gas in the arteries was measured using a blood analyzer. Changes in PaO2, PaO2/FiO2, and lung wet/dry (W/D) weight ratio were carefully compared. ELISA assay was conducted to estimate cell adhesion and inflammation response. Finally, real-time reverse transcription polymerase chain reaction and western blotting assay was used to determine the activation of PI3K/AKT/mTOR pathway.

Results: ARDS in vivo model was successfully constructed by LPS injection. Compared with the sham group, PaO2 and PaO2/FiO2 were significantly lower in the vehicle group, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8 andTNF-αwere significantly increased. After treatment with different doses of sivelestat sodium, we found PaO2, PaO2/FiO2 were prominently increased, while the lung W/D ratio, the lung injury score, NE, VCAM-1, IL-8, TNF-α levels were decreased in the dose-dependent manner. Meanwhile, compared with the vehicle group, the expression levels of Bax, PI3K, Akt and mTOR were significantly lower, and the expression of Bcl-2 was significantly higher after injection with sivelestat sodium.

Conclusion: Sivelestat sodium has an interventional effect on ALI in sepsis by inhibiting the PI3K/AKT/mTOR signalling pathway.

MeSH terms

  • Acute Lung Injury* / drug therapy
  • Acute Lung Injury* / metabolism
  • Acute Lung Injury* / pathology
  • Animals
  • Disease Models, Animal
  • Glycine* / analogs & derivatives
  • Glycine* / pharmacology
  • Glycine* / therapeutic use
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Rats
  • Rats, Sprague-Dawley*
  • Signal Transduction* / drug effects
  • Sulfonamides* / pharmacology
  • Sulfonamides* / therapeutic use
  • TOR Serine-Threonine Kinases* / metabolism

Substances

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • sivelestat
  • Glycine
  • Sulfonamides
  • mTOR protein, rat

Grants and funding

This study was funded by Fund of Science and Technology Bureau of Nantong City, Jiangsu Province (JCZ2022122); Fund of Science and Technology Bureau of Nantong City, Jiangsu Province (JCZ19012); Fund of Research topic of Nantong City Health Commission (WQ2016033).