Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.
Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.
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DOI：
10.1016/j.bcp.2009.10.025
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发表时间：
2010-03-15
影响因子：
5.8
通讯作者：
Hammock, Bruce D.
中科院分区：
文献类型：
--
作者：
Liu, Jun-Yan;Yang, Jun;Inceoglu, Bora;Qiu, Hong;Ulu, Arzu;Hwang, Sung-Hee;Chiamvimonvat, Nipavan;Hammock, Bruce D.
炎症是一个多阶段的过程，其扩张阶段被认为是由急性释放的花生四烯酸（AA）及其代谢产物驱动的。已知抑制环氧合酶（考克斯）、脂氧合酶（LOX）或可溶性环氧化物水解酶（sEH）具有抗炎作用。抑制sEH可稳定细胞色素P450（CYP 450）产物环氧二十碳三烯酸（E3）。在此，我们使用非选择性考克斯抑制剂阿司匹林、5-脂氧合酶活化蛋白（FLAP）抑制剂MK 886和sEH抑制剂t-AUCB选择性地调节脂多糖（LPS）激发的小鼠模型中AA代谢的分支。我们使用代谢组学分析来同时监测每个分支的代表性AA代谢物。除了在选择性调节考克斯、LOX或sEH期间AA级联的分支之间的显著串扰之外，我们证明了共同施用t-AUCB增强了阿司匹林或MK 886的抗炎作用，这通过观察到共同给药导致有利的类二十烷酸谱和更好地控制LPS介导的低血压以及考克斯-2和5-HT的肝蛋白表达来证明。液氧。sEH基因的靶向破坏显示出与t-AUCB产生的特征平行的特征。这些观察结果表明AA级联的三个主要分支之间存在显著水平的串扰，并且它们不是简单的平行通路。这些数据表明，通过药物干预和基因敲除抑制sEH增强了阿司匹林和MK 886的抗炎作用，表明调节多个分支以实现更好的治疗效果的可能性。
Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects.
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影响因子：
5.7
作者：
Cianchi, Fabio;Cortesini, Camillo;Masini, Emanuela
通讯作者：
Masini, Emanuela
影响因子：
8.3
作者：
Imig, JD;Zhao, XY;Hammock, BD
通讯作者：
Hammock, BD
DOI：
10.1111/j.1365-2362.2006.01606.x
发表时间：
2006-03-01
影响因子：
5.5
作者：
Jawien, J;Gajda, M;Korbut, R
通讯作者：
Korbut, R
影响因子：
7.3
作者：
Hwang, Sung Hee;Tsai, Hsing-Ju;Hammock, Bruce D.
通讯作者：
Hammock, Bruce D.
影响因子：
4.8
作者：
CAPDEVILA, JH;FALCK, JR;ESTABROOK, RW
通讯作者：
ESTABROOK, RW