Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-α production through inhibition of Egr-1 expression
Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-α production through inhibition of Egr-1 expression
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DOI：
10.1152/ajpheart.00885.2004
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发表时间：
2005-03-01
影响因子：
4.8
通讯作者：
Okabe, H
中科院分区：
文献类型：
--
作者：
Molor-Erdene, P;Okajima, K;Okabe, H
尿胰蛋白酶抑制剂通过抑制Egr-1表达抑制肿瘤坏死因子-α的产生减少LPS诱导的低血压。美国生理学杂志心脏循环生理学288：H1265-H1271，2005年。首次发表于2004年11月11日; doi：10.1152/ajpheart.00885.2004。虽然尿胰蛋白酶抑制剂（UTI）已被证明可以抑制肿瘤坏死因子（TNF）-α的产生，但其详细机制仍不清楚。本研究旨在阐明体外单核细胞和给予脂多糖（LPS）的大鼠中这种抑制作用的分子机制。在高于100 U/ml的浓度下，UTI抑制LPS（100 ng/ml）刺激的单核细胞产生TNF-α。UTI可抑制LPS刺激的单核细胞早期生长反应因子-1（Egr-1）的表达和细胞外信号调节蛋白激酶1/2的磷酸化。UTI（50，000 U/kg iv）抑制LPS（5 mg/kg iv）诱导的大鼠肺组织Egr-1、TNF-α mRNA和TNF-α水平升高。UTI通过抑制诱导型一氧化氮合酶（iNOS）的肺诱导而抑制LPS诱导的低血压.我们以前证明，抗TNF-α抗体和氨基胍，一种选择性的iNOS抑制剂，减少LPS诱导的低血压在这个动物模型。此外，我们还报道了减少LPS诱导的大鼠凝血异常并不影响该动物模型的炎症反应和低血压。总之，这些观察结果强烈表明，UTI通过抑制单核细胞中细胞外信号调节蛋白激酶1/2-Egr-1途径的活化来抑制LPS诱导的TNF-α的产生，这可能至少部分地有助于通过抑制给予LPS的大鼠中的iNOS诱导来减少低血压。
Urinary trypsin inhibitor reduces LPS- induced hypotension by suppressing tumor necrosis factor-alpha production through inhibition of Egr-1 expression. Am J Physiol Heart Circ Physiol 288: H1265-H1271, 2005. First published November 11, 2004; doi:10.1152/ajpheart.00885.2004.- 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 iv) inhibited LPS (5 mg/kg iv)- 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.