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.
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.
Authors: S M Opal; C J Fisher; J F Dhainaut; J L Vincent; R Brase; S F Lowry; J C Sadoff; G J Slotman; H Levy; R A Balk; M P Shelly; J P Pribble; J F LaBrecque; J Lookabaugh; H Donovan; H Dubin; R Baughman; J Norman; E DeMaria; K Matzel; E Abraham; M Seneff Journal: Crit Care Med Date: 1997-07 Impact factor: 7.598
Authors: Janet S Lee; Charles W Frevert; Gustavo Matute-Bello; Mark M Wurfel; Venus A Wong; Shu-Min Lin; John Ruzinski; Steve Mongovin; Richard B Goodman; Thomas R Martin Journal: Am J Physiol Lung Cell Mol Physiol Date: 2005-07-15 Impact factor: 5.464
Authors: Irshad Ali; Rahul Nanchal; Fouad Husnain; Said Audi; G Ganesh Konduri; John C Densmore; Meetha Medhora; Elizabeth R Jacobs Journal: Pulm Circ Date: 2013-12-04 Impact factor: 3.017