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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/H1265    most recent 00885.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Molor-Erdene, P. Articles by Okabe, H. Search for Related Content PubMed PubMed Citation Articles by Molor-Erdene, P. Articles by Okabe, H.

Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor- production through inhibition of Egr-1 expression

Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

Submitted 27 August 2004 ; accepted in final form 8 November 2004

Although urinary trypsin inhibitor (UTI) has been shown to inhibit tumor necrosis factor (TNF)-- 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- 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 iv) inhibited LPS (5 mg/kg iv)-induced increases in lung tissue levels of Egr-1, TNF- mRNA, and TNF- in rats. UTI inhibited LPS-induced hypotension by inhibiting pulmonary induction of inducible nitric oxide synthase (iNOS). We previously demonstrated that anti-TNF- 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- 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.

septic shock; lipopolysaccharide; early growth response factor-1; inducible nitric oxide synthase

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