Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with a significant number of patients being inadequately controlled by current frontline treatments means that there is a need to define novel therapeutic targets for these conditions1. Here we investigate a member of the G protein-coupled receptor (GPCR) family, FFA4, which responds to free circulating fatty acids, including dietary omega-3 fatty acids found in fish oils2-4. Although usually associated with metabolic responses linked with food intake, we show that FFA4 is expressed in the lung where it is coupled to Gq/11-signalling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated, at least in part, by the release of the prostaglandin PGE2 that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. Importantly, in acute and chronic ozone models of pollution-mediated inflammation, and in house-dust mite and cigarette smoke-induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, whilst this response was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was very similar to that observed in mice and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation. Hence, our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy that might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

中文翻译：

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游离脂肪酸受体FFA4对肺功能的病理生理调节

包括哮喘和慢性阻塞性肺疾病（COPD）在内的炎症性气道疾病的患病率增加，同时大量患者被当前的一线治疗控制不充分，这意味着需要为这些疾病确定新的治疗靶标1。在这里，我们研究了G蛋白偶联受体（GPCR）家族FFA4的成员，该FFA4对自由循环的脂肪酸（包括在鱼油2-4中发现的饮食中omega-3脂肪酸）作出反应。尽管通常与食物摄入相关的代谢反应有关，但我们显示FFA4在肺中表达，并与Gq / 11信号结合。药物样激动剂激活FFA4至少部分介导了鼠气道平滑肌的松弛 释放前列腺素PGE2，随后作用于EP2前列腺素受体。在正常小鼠中，FFA4的激活导致肺部抵抗力降低。重要的是，在污染介导的炎症的急性和慢性臭氧模型中，以及在屋尘螨和香烟烟雾引起的炎症性疾病中，FFA4激动剂可降低呼吸道阻力，而缺乏FFA4表达的小鼠则无此反应。FFA4在人肺中的表达谱与在小鼠中观察到的非常相似，并且对FFA4 / FFA1激动剂的反应也类似地介导了人气道平滑肌松弛。因此，我们的研究提供了证据，即肺部FFA4的药理靶向性以及可能联合激活了FFA4和FFA1，