Effect of Toll-like receptor 4 inhibitor on LPS-induced lung injury

Inflamm Res. 2010 Oct;59(10):837-45. doi: 10.1007/s00011-010-0195-3. Epub 2010 Apr 13.


Objective and design: Toll-like receptor 4 (TLR4) plays important roles in the recognition of lipopolysaccharide (LPS) and the activation of inflammatory cascade. In this study, we evaluated the effect of TAK-242, a selective TLR4 signal transduction inhibitor, on acute lung injury (ALI).

Materials and methods: C57BL/6J mice were intravenously treated with TAK-242 15 min before the intratracheal administration of LPS or Pam3CSK4, a synthetic lipopeptide. Six hours after the challenge, bronchoalveolar lavage fluid was obtained for a differential cell count and the measurement of cytokine and myeloperoxidase levels. Lung permeability and nuclear factor-kappaB (NF-kappaB) DNA binding activity were also evaluated.

Results: TAK-242 effectively attenuated the neutrophil accumulation and activation in the lungs, the increase in lung permeability, production of inflammatory mediators, and NF-kappaB DNA-binding activity induced by the LPS challenge. In contrast, TAK-242 did not suppress inflammatory changes induced by Pam3CSK4.

Conclusion: TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced*
  • Acute Lung Injury / drug therapy
  • Acute Lung Injury / immunology
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Chemokines / immunology
  • Cytokines / immunology
  • Humans
  • Inflammation Mediators / immunology
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / immunology


  • Chemokines
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Sulfonamides
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate