TAK-242 attenuates acute cigarette smoke-induced pulmonary inflammation in mouse via the TLR4/NF-κB signaling pathway

Biochem Biophys Res Commun. 2016 Apr 8;472(3):508-15. doi: 10.1016/j.bbrc.2016.03.001. Epub 2016 Mar 2.

Abstract

The present study determined the effect of TAK-242 on attenuating acute cigarette smoke induced pulmonary inflammation and attempted to dissect its underlying mechanisms of action. When administered to the C57BL/6J mice after a 3 days period of cigarettes exposure,TAK-242 significantly decreased the accumulation of macrophages, neutrophils, lymphocytes and DCs, and upregulation of IL-6, IL-8 and TNF-α in BAL fluid and lungs in a dose-dependent manner, except MCP-1, IL-1β and IFN-γ, which demonstrated that TAK-242 inhibits release of various inflammatory mediators induced by cigarette smoke. TAK-242 also significantly suppressed the expression of TLR4, MyD88 and the activation of NF-κB in lungs, suggesting that TAK-242-mediated inhibition occurred largely through the TLR4/NF-κB signal pathway. Our results support TAK-242 as a potent therapeutic agent in the treatment of cigarette smoke induced-pulmonary inflammation, and warrants further pharmaceutical investigation.

Keywords: Inflammation; TAK-242; TLR4.

MeSH terms

  • Acute Disease
  • Animals
  • Dose-Response Relationship, Drug
  • Lung
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Pneumonia / drug therapy*
  • Pneumonia / etiology
  • Pneumonia / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sulfonamides / administration & dosage*
  • Tobacco Smoke Pollution / adverse effects*
  • Toll-Like Receptor 4 / immunology*
  • Treatment Outcome

Substances

  • NF-kappa B
  • Sulfonamides
  • Tlr4 protein, mouse
  • Tobacco Smoke Pollution
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate