Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury |
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Authors: | Togbe Dieudonnée Schnyder-Candrian Silvia Schnyder Bruno Doz Emilie Noulin Nicolas Janot Laure Secher Thomas Gasse Pamela Lima Carla Coelho Fernando Rodrigues Vasseur Virginie Erard François Ryffel Bernhard Couillin Isabelle Moser Rene |
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Institution: | Molecular Immunology and Embryology, University of Orléans and CNRS UMR6218, Transgenose Institute, Orleans, France;, Key-Obs S.A., Orleans, France;, Biomedical Research Foundation, SBF, Matzingen,;and IBR, Institute for Biopharmaceutical Research, Matzingen, Switzerland |
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Abstract: | 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. |
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Keywords: | lung inflammation MAPK TNF Toll-like receptor |
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