Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4.
Inhalation of toxic doses of ozone is associated with a sterile inflammatory response characterized by an accumulation of macrophages in the lower lung which are activated to release cytotoxic/proinflammatory mediators that contribute to tissue injury. Toll-like receptor 4 (TLR4) is a pattern recognition receptor present on macrophages that has been implicated in sterile inflammatory responses. In the present studies we used TLR4 mutant C3H/HeJ mice to analyze the role of TLR4 in ozone-induced lung injury, oxidative stress and inflammation. Acute exposure of control C3H/HeOuJ mice to ozone (0.8ppm for 3h) resulted in increases in bronchoalveolar lavage (BAL) lipocalin 24p3 and 4-hydroxynonenal modified protein, markers of oxidative stress and lipid peroxidation. This was correlated with increases in BAL protein, as well as numbers of alveolar macrophages. Levels of surfactant protein-D, a pulmonary collectin known to regulate macrophage inflammatory responses, also increased in BAL following ozone inhalation. Ozone inhalation was associated with classical macrophage activation, as measured by increased NF-κB binding activity and expression of TNFα mRNA. The observation that these responses to ozone were not evident in TLR4 mutant C3H/HeJ mice demonstrates that functional TLR4 contributes to ozone-induced sterile inflammation and macrophage activation.
Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA.
Agnieszka J
AJ
Connor
Jeffrey D
JD
Laskin
Debra L
DL
Laskin
D000209:Acute-Phase Proteins / Q000032:analysis; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D007249:Inflammation / Q000139:chemically induced*; D015227:Lipid Peroxidation; D000071068:Lipocalin-2; D054834:Lipocalins / Q000032:analysis; D055370:Lung Injury / Q000139:chemically induced*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000032:analysis; D018384:Oxidative Stress; D010126:Ozone / Q000633:toxicity*; D037663:Pulmonary Surfactant-Associated Protein D / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000209:Acute-Phase Proteins; D000447:Aldehydes; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D015513:Oncogene Proteins; D037663:Pulmonary Surfactant-Associated Protein D; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D010126:Ozone; C027576:4-hydroxy-2-nonenal