title: Distinct responses of lung and liver macrophages to acute endotoxemia: role of toll-like receptor 4.
abstract: Exposure to excessive quantities of bacterial-derived lipopolysaccharide (LPS) is associated with injury to the lung and the liver. Macrophages are thought to play a key role in the pathogenic response to LPS by releasing proinflammatory/cytotoxic mediators. Macrophage responses to LPS are mediated in large part by toll-like receptor 4 (TLR4). In the present studies we used C3H/HeJ mice, which possess a mutated nonfunctional TLR4, to examine its role in lung and liver macrophage responses to acute endotoxemia induced by LPS administration. Treatment of control C3H/HeOuJ mice with LPS (3 mg/ml, i.p.) was associated with a significant increase in the number of macrophages in both the lung and the liver. This was most prominent after 48 h, and was preceded by expression of proliferating cell nuclear antigen (PCNA), suggesting that macrophage proliferation contributes to the response. In liver, but not lung macrophages, LPS administration resulted in a rapid (within 3 h) increase in mRNA expression of Mn superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), key enzymes in antioxidant defense. In contrast, HO-1 protein expression decreased 3 h after LPS administration in liver macrophages, while in lung macrophages it increased. mRNA expression of enzymes mediating the biosynthesis of eicosanoids, including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), but not 12/15-lipoxygenase (LOX), was upregulated in liver macrophages 3-24 h after LPS, with no effect on lung macrophages. However, COX-2 protein expression increased in both cell types. Loss of functional TLR4 significantly blunted the effects of LPS. Thus, no major changes were observed after LPS administration in the number of lung and liver macrophages recovered from TLR4 mutant mice, or on expression of PCNA. Increases in HO-1, MnSOD, COX-2 and PGES-1 mRNA expression in liver macrophages were also reduced in these mice. Conversely, in lung macrophages, loss of functional TLR4 resulted in increased expression of COX-2 protein and 12/15-LOX mRNA. These results demonstrate distinct lung and liver macrophage responses to acute endotoxemia are mediated, in part, by functional TLR4.
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA.
authors.forename: Agnieszka J
authors.initials: AJ
authors.lastname: Connor
authors.forename: Li C
authors.initials: LC
authors.lastname: Chen
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Joseph
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D019446:Endotoxemia / Q000276:immunology*; D004789:Enzyme Activation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000276:immunology; D008168:Lung / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C475064:12-15-lipoxygenase; D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse