Pathophysiological regulation of lung function by the free fatty acid receptor FFA4.
Pathophysiological regulation of lung function by the free fatty acid receptor FFA4.
复制标题
游离脂肪酸受体 FFA4 对肺功能的病理生理调节。
DOI：
10.1126/scitranslmed.aaw9009
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发表时间：
2020
影响因子：
17.1
通讯作者：
Prihandoko R
中科院分区：
文献类型：
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作者：
Prihandoko R
包括哮喘和慢性阻塞性肺病 (COPD) 在内的炎症性气道疾病的患病率增加，加上当前一线治疗对疾病控制不足，意味着需要确定这些疾病的治疗目标。在这里，我们研究了 G 蛋白偶联受体家族的成员 FFA4，它对游离循环脂肪酸（包括鱼油中的膳食 omega-3 脂肪酸）做出反应。我们发现，虽然 FFA4 通常与食物摄入相关的代谢反应相关，但它在肺部表达，并与 Gq/11 信号传导耦合。药物样激动剂激活 FFA4 会导致小鼠气道平滑肌松弛，至少部分是通过随后作用于 EP2 前列腺素受体的前列腺素 E2 (PGE2) 的释放介导的。在正常小鼠中，FFA4 的激活导致肺阻力下降。在污染介导的炎症、屋尘螨和香烟烟雾诱发的炎症性疾病的急性和慢性臭氧模型中，FFA4 激动剂可以降低气道阻力，而缺乏 FFA4 表达的小鼠则不存在这种反应。人肺中 FFA4 的表达谱与小鼠中观察到的相似，并且对 FFA4/FFA1 激动剂的反应类似地介导离体人气道平滑肌松弛。我们的研究提供了证据，表明肺 FFA4 的药理学靶向，以及可能联合激活 FFA4 和 FFA1，具有体内功效，并且可能在治疗与炎症性气道疾病（如哮喘和慢性阻塞性肺病）相关的支气管收缩方面具有治疗价值。
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 Gq/11signaling. 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 EP2prostanoid 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.