title: Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-alpha production through inhibition of Egr-1 expression.
abstract: Although urinary trypsin inhibitor (UTI) has been shown to inhibit tumor necrosis factor (TNF)-alpha- production, the detailed mechanism(s) remains unclear. This study was undertaken to elucidate the molecular mechanism(s) underlying this inhibitory effect in monocytes in vitro and in rats given lipopolysaccharide (LPS). TNF-alpha production by monocytes stimulated with LPS (100 ng/ml) was inhibited by UTI at concentrations higher than 100 U/ml. Expression of early growth response factor-1 (Egr-1) and phosphorylation of extracellular signal-regulated protein kinases 1/2 in monocytes stimulated with LPS were inhibited by UTI. UTI (50,000 U/kg i.v.) inhibited LPS (5 mg/kg i.v.)-induced increases in lung tissue levels of Egr-1, TNF-alpha mRNA, and TNF-alpha in rats. UTI inhibited LPS-induced hypotension by inhibiting pulmonary induction of inducible nitric oxide synthase (iNOS). We previously demonstrated that anti-TNF-alpha antibody and aminoguanidine, a selective inhibitor of iNOS, reduced LPS-induced hypotension in this animal model. Furthermore, we also reported that reduction of LPS-induced coagulation abnormalities in rats did not affect inflammatory responses and hypotension in this animal model. Taken together, these observations strongly suggested that UTI inhibited LPS-induced production of TNF-alpha by inhibiting activation of the extracellular signal-regulated protein kinases 1/2-Egr-1 pathway in monocytes, which might at least partly contribute to reduction of hypotension through inhibition of iNOS induction in rats given LPS.
authors.affiliation: Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University., 1-1-1 Honjo, Kumamoto, 860-0811, Japan.
authors.forename: Perenlei
authors.initials: P
authors.lastname: Molor-Erdene
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Isobe
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Uchiba
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okabe
mesh_terms: D000818:Animals; D004347:Drug Interactions; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C028665:urinastatin