Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to G_q/11 signaling. 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 E₂ (PGE₂) that subsequently acts on EP₂ prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

当前的一线治疗增加了包括哮喘和慢性阻塞性肺疾病（COPD）在内的炎性气道疾病的流行，以及疾病控制不力，这意味着需要为这些疾病确定治疗目标。在这里，我们研究了G蛋白偶联受体家族FFA4的成员，该成员对自由循环的脂肪酸（包括鱼油中的饮食中omega-3脂肪酸）作出反应。我们显示，虽然FFA4通常与与食物摄入相关的代谢反应相关，但在肺中与G _{q / 11}信号偶联时表达。药物样激动剂对FFA4的激活会至少部分由前列腺素E ₂（PGE ₂的释放）介导的鼠气道平滑肌松弛），随后根据EP ₂起作用前列腺素受体。在正常小鼠中，FFA4的激活导致肺部抵抗力降低。在污染介导的炎症，屋尘螨和香烟烟雾引起的炎症性疾病的急性和慢性臭氧模型中，FFA4激动剂可降低呼吸道阻力，而缺乏FFA4表达的小鼠缺乏这种反应。FFA4在人肺中的表达谱与在小鼠中观察到的相似，并且对FFA4 / FFA1激动剂的应答类似地介导了离体的人气道平滑肌松弛。我们的研究提供了证据，即肺部FFA4的药理靶向作用以及FFA4和FFA1的联合激活可能具有体内功效，并且在治疗与炎症性气道疾病（如哮喘和COPD）相关的支气管收缩中可能具有治疗价值。