Relationship between Bradykinin-induced relaxation in human bronchi and endogenous epoxy-eicosanoid synthesis

Physiology 2012 (Edinburgh) (2012) Proc Physiol Soc 27, PC41

Poster Communications: Relationship between Bradykinin-induced relaxation in human bronchi and endogenous epoxy-eicosanoid synthesis

Y. Tabet1, M. Sirois2, C. Sirois2, E. Rizcallah3, . Rousseau1

1. Physiology and Biophysics, UniversitÚ de Sherbrooke, Sherbrooke, Quebec, Canada. 2. Thoracic Surgery Division, UniversitÚ de Sherbrooke, Sherbrooke, Quebec, Canada. 3. Department of Pathology, UniversitÚ de Sherbrooke, Sherbrooke, Quebec, Canada.

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Asthma is an inflammatory disease characterised by bronco-constriction and increased mucus secretion which may be modulated by endogenous lipids (Prostaglandins, Leukotrienes and Eicosanoids). Epoxy-eicosanoids (EETs) have been shown to play key roles in inflammation resolution and broncho-relaxation. EETs are produced in epithelial cells by CYP 450 epoxygenase and are metabolized by soluble Epoxide Hydrolase (sEH) in non-active dihydroxyeicosatrienoic acid (DHET). While the mode of action and physiological involvements of EETs are well established (Morin et al, 2007, 2008, 2010 AJRCMB), it is still unknown what triggers their endogenous production. The relaxing effect of Bradykinin is already known to be related to endogenous production of epithelial derived hyperpolarising factors (EpDHF), nitric oxide (NO) and Prostacyclin (PgI2). Because of their effects on membrane potential, EETs have been reported to be a candidate for EpDHF. Working hypothesis: There is a relationship between Bradykinin stimulation and endogenous EET production in human bronchi. Specific objectives: 1) To quantify relaxing effects of exogenous Bradykinin and 14,15-EET on human bronchi. 2) To assess the effects of various enzymatic inhibitors on the relaxing effects of Bradykinin and 14,15-EET on human bronchi. 3) To evaluate the hyperpolarising effects of these compounds on airway smooth muscle cells (ASMC) in presence (or absence) of specific CYP 450 epoxygenase inhibitors. Methods and Results: Isometric tension measurements were performed on distal human bronchi recovered from pulmonary resections, in an isolated organ bath system. All procedures were approved by the Ethics Committee of our institution (protocol Nb: 05-088-S1-R2). 1 µM of Bradykinin or 1 µM of 14,15-EET induced 50% relaxation (n=15) of tension induced by 30 nM of U-46619 (a Thromboxane A2 analogue). These relaxing effects of Bradykinin were reduced by 50% upon addition of 10 nM Iberiotoxin (a BKCa channel blocker, n=6), by 40% following addition of 10 µM 14,15-EEZE (an EET antagonist, n=9) and by 35% with 3 µM MS-PPOH (an epoxygenase inhibitor, n=15). Hence, Bradykinin and EET display net hyperpolarising effects on ASMC, which are related to the activation of BKCa channels and yield relaxation. Moreover, preliminary results indicate that 3 µM MS-PPOH reduces the hyperpolarising effects of Bradykinin (n=2) on ASMC by 50%, as assessed by microelectrode measurements. All results were subjected to a Wilcoxon Signed Rank test and were significant (p<0.05). Together, our data support the working hypothesis and suggest a relationship between Bradykinin and endogenous EET production. Because of their potent anti-inflammatory and relaxing properties, epoxy-eicosanoids signalling is a promising target in asthma and COPD.



Where applicable, experiments conform with Society ethical requirements.

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