Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L675-82. doi: 10.1152/ajplung.00427.2010. Epub 2011 Aug 5.
Epoxyeicosatrienoic acid (EET) and thromboxane A(2) are arachidonic acid derivatives. The former has initially been defined as an epithelium-derived hyperpolarizing factor displaying broncho-relaxing and anti-inflammatory properties, as recently demonstrated, whereas thromboxane A(2) induces vaso- and bronchoconstriction upon binding to thromboxane-prostanoid (TP)-receptor. EETs, however, are quickly degraded by the soluble epoxide hydrolase (sEH) into inactive diol compounds. The aim of this study was to investigate the effects of 14,15-EET on TP-receptor activation in human bronchi. Tension measurements performed on native bronchi from various species, acutely treated with increasing 14,15-EET concentrations, revealed specific and concentration-dependent relationships as well as a decrease in the tension induced by 30 nM U-46619, used as a synthetic TP-receptor agonist. Interestingly, acute treatments with 3 μM N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, an epoxygenase inhibitor, which minimizes endogenous production of EET, resulted in an increased reactivity to U-46619. Furthermore, we demonstrated that chronic treatments with trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a sEH inhibitor, reduced human bronchi reactivity to U-46619. During our tension measurements, we also observed that human bronchi generated small-amplitude contractions; these spontaneous activities were reduced upon acute 14,15-EET treatments in the presence of t-AUCB. Altogether, these data demonstrate that endogenous and exogenous 14,15-EET could interfere with the activation of TP-receptors as well as with spontaneous oscillations in human airway smooth muscle tissues.
环氧二十碳三烯酸（EET）和血栓烷 A(2) 是花生四烯酸的衍生物。前者最初被定义为上皮细胞衍生的超极化因子，具有支气管舒张和抗炎特性，正如最近所证明的那样，而血栓烷 A(2) 与血栓烷-前列腺素 (TP) 受体结合后会引起血管和支气管收缩。然而，EETs 很快被可溶性环氧化物水解酶 (sEH) 降解为无活性的二醇化合物。本研究旨在研究 14,15-EET 对人支气管中 TP 受体激活的影响。对来自不同物种的天然支气管进行张力测量，用递增浓度的 14,15-EET 急性处理，揭示了特异性和浓度依赖性关系，以及用 30 nM U-46619 诱导的张力降低，U-46619 用作合成 TP 受体激动剂。有趣的是，用 3 μM N-(甲基磺酰基)-2-(2-丙炔氧基)-苯己酰胺（一种环氧合酶抑制剂，可最大限度地减少内源性 EET 的产生）进行急性处理，导致对 U-46619 的反应性增加。此外，我们证明，用反式-4-[4-(3-金刚烷-1-基-脲基)-环己氧基]-苯甲酸（t-AUCB），一种 sEH 抑制剂，进行慢性处理，降低了人支气管对 U-46619 的反应性。在我们的张力测量过程中，我们还观察到人支气管产生小振幅收缩；这些自发活动在 t-AUCB 存在下急性 14,15-EET 处理时减少。总的来说，这些数据表明内源性和外源性 14,15-EET 可能干扰 TP 受体的激活以及人气道平滑肌组织中的自发振荡。
