title: Lung, spleen, and kidney are the major places for inducible nitric oxide synthase expression in endotoxic shock: role of p38 mitogen-activated protein kinase in signal transduction of inducible nitric oxide synthase expression.
abstract: Bacterial lipopolysaccharide (LPS) is known to induce endotoxic shock with inducible nitric oxide (NO) synthase (iNOS) expression and NO production. However, the major place for NO production in shock remains unclear. Although there is some literature about p38 mitogen-activated protein kinase (MAPK) in regulating LPS-induced iNOS expression, the results are contradictory. To interpret the precise cell mechanism and the role of p38 MAPK in the expression of iNOS during endotoxic shock, we carried out the following investigations. A severe endotoxic shock model was reproduced in mice 6 h after LPS injection. The plasma NO level was increased in a dose- and time-dependent manner after LPS stimulation and was suppressed by administration of SB203580 [4-(4-fluorophenyl)-2-4-methylsulfonylphenyl-5-(4-pyridyl) imidazole], a highly specific inhibitor of p38 MAPK. The iNOS expression was increased in many organs, including heart, liver, spleen, lung, gut, and kidney in endotoxic shock. Among them, the highest expression of iNOS mRNA and protein was in the lung, moderate expression was in the spleen and kidney, and the lowest expression was in the heart, gut, and liver. The level of expression in lung was 5.5 times that of iNOS mRNA and was 3.1 times that of iNOS protein than in heart, and 1.6 and 1.8 times that of iNOS mRNA and 1.7 and 1.4 times that of iNOS protein than in spleen and kidney, respectively. The p38 MAPK activity increased after LPS injection, and SB203580 markedly reduced LPS-induced expressions of iNOS protein and mRNA in the lung. The results indicates that lung, spleen, and kidney are the major places for iNOS expression in endotoxic shock and are important therapeutic target organs for attenuating NO production in shock treatment.
authors.affiliation: Department of Pathophysiology, The First Military Medical University, Guangzhou, China.
authors.forename: Wenhong
authors.initials: W
authors.lastname: Kan
authors.forename: Ke-seng
authors.initials: KS
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yan
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.forename: Jingzhen
authors.initials: J
authors.lastname: Wang
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Qin
authors.forename: Xuliang
authors.initials: X
authors.lastname: Huang
authors.forename: Shiwen
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic; D015398:Signal Transduction; D013154:Spleen / Q000201:enzymology*; D013997:Time Factors; D014018:Tissue Distribution; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D017931:DNA Primers; D004731:Endotoxins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580