Inhibition of soluble epoxide hydrolase does not protect against endotoxin-mediated hepatic inflammation.
Inhibition of soluble epoxide hydrolase does not protect against endotoxin-mediated hepatic inflammation.
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DOI：
10.1124/jpet.108.142398
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Kroetz DL
中科院分区：
文献类型：
--
作者：
Fife KL;Liu Y;Schmelzer KR;Tsai HJ;Kim IH;Morisseau C;Hammock BD;Kroetz DL
环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）是由细胞色素P450（CYP 450）催化的花生四烯酸环氧化反应产生的，是一种重要的生物学调节剂。雌二醇的主要消除途径是通过可溶性环氧化物水解酶（sEH）催化代谢为二羟基二十碳三烯酸（DHEA）。基于先前的研究表明，EH具有抗炎作用，我们假设慢性抑制sEH会减弱体内脂多糖（LPS）诱导的炎症反应。sEH抑制剂12-（3-金刚烷-1-基-脲基）-十二烷酸（AUDA）、AUDA的聚乙二醇酯（AUDA-PEG）和1-金刚烷-1-基-3-（5-（2-（2-乙氧基乙氧基）乙氧基）戊基）脲（AEPU）的连续给药导致对抑制剂和靶点接合的稳健暴露，如抑制剂治疗6天后血浆EET/DHET比率的显著增加所证明的。然而，sEH抑制剂治疗与肝脏中LPS诱导的炎症基因表达的减弱无关，AUDA不能保护LPS诱导的中性粒细胞浸润。此外，缺乏sEH表达且血浆EET/DHET比率显着增加的Ephx 2-/-小鼠无法免受LPS诱导的炎症基因表达或肝脏中性粒细胞积聚的影响。LPS确实对sEH的表达和功能有影响，这从Ephx 2 mRNA的显着下调和LPS处理后四小时血浆EET/DHET比率的显着变化中可以看出。总之，没有证据表明增加体内EET水平可以调节LPS诱导的肝脏炎症反应。然而，LPS确实对血浆类花生酸水平和肝脏Ephx 2表达具有显著影响，表明体内EET水平响应于炎症信号而被调节。
Epoxyeicosatrienoic acids (EETs) are derived from cytochrome P450 (CYP)-catalyzed epoxygenation of arachidonic acid and have emerged as important mediators of numerous biological effects. The major elimination pathway for EETs is through soluble epoxide hydrolase (sEH) catalyzed metabolism to dihydroxyeicosatrienoic acids (DHETs). Based on previous studies showing that EETs have anti-inflammatory effects, we hypothesized that chronic inhibition of sEH would attenuate a lipopolysaccharide (LPS)-induced inflammatory response in vivo. Continuous dosing of the sEH inhibitors 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a polyethylene glycol ester of AUDA (AUDA-PEG), and 1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea (AEPU) resulted in robust exposure to the inhibitor and target engagement, as evidenced by significant increases in plasma EET/DHET ratios following six days of inhibitor treatment. However, sEH inhibitor treatment was not associated with an attenuation of LPS-induced inflammatory gene expression in the liver and AUDA did not protect from LPS-induced neutrophil infiltration. Furthermore, Ephx2 −/− mice that lack sEH expression and have significantly increased plasma EET/DHET ratios were not protected from LPS-induced inflammatory gene expression or neutrophil accumulation in the liver. LPS did have an effect on sEH expression and function, as evident from a significant downregulation of Ephx2 mRNA and a significant shift in plasma EET/DHET ratios four hours after LPS treatment. In conclusion, there was no evidence that increasing EET levels in vivo could modulate an LPS-induced inflammatory response in the liver. However, LPS did have significant effects on plasma eicosanoid levels and hepatic Ephx2 expression, suggesting that in vivo EET levels are modulated in response to an inflammatory signal.
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影响因子：
2.9
作者：
Fang, X;Weintraub, NL;Spector, AA
通讯作者：
Spector, AA
DOI：
10.1111/j.1432-1033.1994.tb19048.x
发表时间：
1994-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
RODEWALD, E;TIBES, U;SCHEUER, W
通讯作者：
SCHEUER, W
影响因子：
20.1
作者：
Seubert, John M.;Sinal, Christopher J.;Zeldin, Darryl C.
通讯作者：
Zeldin, Darryl C.
影响因子：
4.8
作者：
Luria, Ayala;Weldon, Steven M.;Hammock, Bruce D.
通讯作者：
Hammock, Bruce D.
影响因子：
8.3
作者：
Imig, JD;Zhao, XY;Hammock, BD
通讯作者：
Hammock, BD