Nording Malin L, Yang Jun, Hoang Laura, Zamora Vanessa, Uyeminami Dale, Espiritu Imelda, Pinkerton Kent E, Hammock Bruce D, Luria Ayala
Department of Chemistry, Umeå University, 901 87 Umeå, Sweden; Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA.
Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA.
J Metabolomics. 2015 Apr;1. doi: 10.7243/2059-0008-1-1. Epub 2015 Apr 4.
The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.
慢性阻塞性肺疾病（COPD）潜在的炎症过程可能由接触烟草烟雾（TS）引起。先前的研究表明，环氧二十碳三烯酸（EETs）具有良好的抗炎特性，因此，在由TS暴露引起的急性和亚慢性炎症小鼠模型中，研究了通过抑制可溶性环氧化物水解酶（sEH）来稳定EETs和其他脂肪酸环氧化物的情况。在整个TS暴露期间，通过饮用水给予强效sEH抑制剂1-(1-甲基磺酰基-哌啶-4-基)-3-(4-三氟甲氧基-苯基)-脲（TUPS）。为了评估TUPS对药物靶点的作用，采用串联质谱法对多种脂肪酸代谢物进行生物活性脂质分析，这些代谢物包括EETs及其源自花生四烯酸的相应二醇（DHETs），以及源自其他脂肪酸的环氧化物和二醇。与未治疗的小鼠相比，用sEH抑制剂治疗的小鼠中，几种（但不是全部）血浆环氧化物/二醇比率有所增加，这表明sEH除了花生四烯酸外，还涉及更多脂肪酸前体，发挥着更广泛的作用。这项研究支持通过生物活性脂质分析探索的环氧化物/二醇比率的定性应用，以表明在与COPD相关的TS暴露小鼠模型中药物靶点的作用，这可能对未来sEH的治疗干预产生影响。
