Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that an omega-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRgamma) and Docosahexaenoic acid (DHA), an omega-3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRgamma was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRgamma knockdown in naive mice led to spontaneous asthma like features whereas RXRgamma knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRgamma binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRalpha expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.

中文翻译：

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营养补充二十二碳六烯酸（DHA）调节哮喘中类固​​醇不敏感

现在发现类固醇反应性较差的哮喘患者更频繁地使用卫生服务，并且不成比例地增加了社会经济负担。先前我们已经表明，omega-6脂肪酸代谢物会导致小鼠出现严重的，类固醇不敏感的哮喘样疾病。在这里，我们调查了类维生素A x受体γ（RXRgamma）和二十二碳六烯酸（DHA），即RXR的ω-3脂肪酸类毒素配体，对哮喘患者中类固醇不敏感特征的作用。发现RXRgamma在人哮喘患者和类固醇不敏感过敏性气道炎症小鼠的肺部减少。幼稚小鼠中的RXRgamma抑制可导致自发性哮喘样特征，而过敏性小鼠中的RXRgamma抑制可导致类固醇不敏感的哮喘特征。我们观察到，虽然RXRgamma结合糖皮质激素受体（GR）基因并调节其转录，但DHA增加了人类支气管上皮细胞中GRalpha的表达，并逆转了过敏性气道炎症小鼠的类固醇不敏感特征。二十二碳六烯酸（DHA），一种RXR的配体，在类固醇不敏感哮喘患者的血清中减少。我们得出的结论是，DHA可能被证明是治疗类固醇不敏感哮喘的有希望的类固醇敏化剂。