Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury.
Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation.
Molecular Immunology and Embryology, University of Orléans and CNRS UMR6218, Transgenose Institute, Orleans, France.
Dieudonnée
D
Togbe
Silvia
S
Schnyder-Candrian
Bruno
B
Schnyder
Emilie
E
Doz
Nicolas
N
Noulin
Laure
L
Janot
Thomas
T
Secher
Pamela
P
Gasse
Carla
C
Lima
Fernando Rodrigues
FR
Coelho
Virginie
V
Vasseur
François
F
Erard
Bernhard
B
Ryffel
Isabelle
I
Couillin
Rene
R
Moser
D000818:Animals; D016084:Bronchoconstriction; D016207:Cytokines / Q000276:immunology; D004789:Enzyme Activation; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases