The role of Toll-like receptor 4 in environmental airway injury in mice.
Inhalation of toxins commonly found in air pollution contributes to the development and progression of asthma and environmental airway injury. In this study, we investigated the requirement of toll-like receptor 4 (TLR4) in mice for pulmonary responses to three environmental toxins: aerosolized lipopolysaccharide, particulate matter (residual oil fly ash), and ozone. The physiologic and biologic responses to these toxins were evaluated by the extent of airway responsiveness, neutrophil recruitment to the lower respiratory tract, changes in inflammatory cytokines, and the concentration of protein in the lavage fluid. Genetically engineered, TLR4-deficient mice (C57BL/6(TLR4-/-)) were unresponsive to inhaled lipopolysaccharide, except for minimal increases in some inflammatory cytokines. In contrast, C57BL/6(TLR4-/-) mice did not differ from wild-type mice in their airway response to instilled residual oil fly ash or acute ozone exposure; however, we found that, despite a robust inflammatory response, C57BL/6(TLR4-/-) mice are protected against the development of airway hyperresponsiveness after subchronic ozone exposure. These data demonstrate in the mouse that the requirement of TLR4 for pulmonary inflammation depends on the nature of the toxin and appears specific to toxin and exposure conditions.
Hollingsworth
John W
JW
Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, NC 27710, USA. holli017@mc.duke.edu
Cook
Donald N
DN
Brass
David M
DM
Walker
Julia K L
JK
Morgan
Daniel L
DL
Foster
W Michael
WM
Schwartz
David A
DA
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002244:Carbon; D060729:Coal Ash; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D018876:Environmental Illness / Q000139:chemically induced / Q000378:metabolism*; D004926:Escherichia coli; D019570:Inhalation Exposure; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010126:Ozone; D052638:Particulate Matter; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D012140:Respiratory Tract Diseases / Q000139:chemically induced / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D060729:Coal Ash; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D052638:Particulate Matter; D011506:Proteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D010126:Ozone; D002244:Carbon