Grant: Travel Awards - Institute Community Support

Asthma is an inflammatory disease characterised by bronco-constriction and increased mucus secretion which could be modulated by endogenous lipids (Prostaglandins, Leukotrienes and Eicosanoids). Epoxy-eicosanoids (EET) are known to play key roles in inflammation resolution and bronco-relaxation. Their mode of action and physiological mechanisms are well established (Morin et al, 2007, 2009, 2010 AJRCMB), however we still don't know what triggers their endogenous production. Our hypothesis is that there is a relationship between Bradykinin effects and the endogenous EET bioavailability in human bronchi. Our specifics objectives are: 1) To quantify relaxing effects of Bradykinin and exogenous 14,15-EET on human bronchi. 2) To compare the effects of different inhibitors on the relaxing effects of Bradykinin and 14,15-EET on human bronchi. 3) To evaluate the hyperpolarizing effects of Bradykinin and 14,15-EET on airway smooth muscle cell (ASMC) in presence or not of specific CYP 450 epoxygenase inhibitors. Isometric tension measurements were performed on human bronchi originating from pulmonary resections. 1 uM of Bradykinin or 1 uM of 14,15-EET induce 50% relaxation on tension induced by 30 nM of U-46619 (Thromboxane A2 analog). The Bradykinin relaxing effects are reduced by 50% upon 10 nM Iberiotoxin treatment, which is a BKca blocker, by 40% following addition of 10 uM 14,15-EEZE which is an EET antagonist and by 35% with 3 uM MS-PPOH, which is a CYP 450 epoxygenase inhibitor. Hence, both Bradykinin and EET display net hyperpolarizing effects on ASMC, which is related to the activation of BKca conductances and lead to relaxation. Because of their potent anti-inflammatory and relaxing properties, EET regioisomers, which are metabolized by soluble Epoxide Hydrolase (sEH), are a promising target in COPD and asthma. A better understanding of the EET endogenous production is mandatory to develop a specific therapeutic strategy targeting these pathways.