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


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.


CONCLUSIONS
TAK-242 may be a promising therapeutic agent for ALI, especially injuries associated with pneumonia caused by Gram-negative bacteria.
Seki
Hiroyuki
H
Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
Tasaka
Sadatomo
S
Fukunaga
Koichi
K
Shiraishi
Yoshiki
Y
Moriyama
Kiyoshi
K
Miyamoto
Keisuke
K
Nakano
Yasushi
Y
Matsunaga
Naoko
N
Takashima
Katsunori
K
Matsumoto
Tatsumi
T
Ii
Masayuki
M
Ishizaka
Akitoshi
A
Takeda
Junzo
J
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
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