Improved bioavailability of epoxyeicosatrienoic acids reduces TP-receptor agonist-induced tension in human bronchi

Abstract

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.

Relationship between bradykinin-induced relaxation and endogenous epoxyeicosanoid synthesis in human bronchi

“…It was previously shown that a 15-min pretreatment with 3 M MS-PPOH (a CYP450 epoxygenase inhibitor that minimizes the endogenous production of EETs) (23, 24) significantly increased U-46619-induced tension in human bronchi (31). We now demonstrate that CYP450 epoxygenase inhibition, which leads to a decrease in EET bioavailability, significantly reduced BK-induced relaxation (as reported in Fig.…”

“…In contrast to our expectations, a 10-min pretreatment with the EET antagonist 14,15-EEZE had no significant effect on U-46619-induced tension. It was anticipated that the inhibition of the effect of EET by the antagonist would increase TP receptor-induced tension because of the potential opposing effects between these lipid mediators (31). On the other hand, 14,15-EEZE pretreatment did have a significant inhibitory effect on BK-induced relaxation.…”

Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice

“…EETs have various beneficial effects against inflammation, platelet aggregation, and migration of vascular smooth muscle cells (Xu, et al, 2011). EETs are involved in pulmonary diseases, such as pulmonary hypertension, allergic asthma, and bronchi (Feng, et al, 2013, Loot and Fleming, 2011, Norton, Wijesinghe, Dellinger, Sturgill, Zhou, Barbour, Chalfant, Conrad and Kepley, 2012, Senouvo, et al, 2011). EETs can be further metabolized by sEH to DHETs, which possess much lesser biological activities than EETs (Lee, et al, 2013).…”

Soluble epoxide hydrolase: Gene structure, expression and deletion

“…In humans, sEH protein was identified in lysates prepared from the parenchyma, bronchi, and pulmonary artery (Senouvo et al, 2011). Patients with asthma exhibit a higher expression of sEH in the bronchi, judged by immunohistochemistry (Morin et al, 2010).…”