Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease.
Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease.
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DOI：
10.1152/ajplung.00396.2015
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发表时间：
2016-06
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通讯作者：
J. Siddesha;Emily M Nakada;Bethany Mihavics;S. Hoffman;G. K. Rattu;Nicolas Chamberlain;Jonathon M Cahoon;K. Lahue;N. Daphtary;M. Aliyeva;David G. Chapman;Dhimant H Desai;M. Poynter;V. Anathy
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作者：
J. Siddesha;Emily M Nakada;Bethany Mihavics;S. Hoffman;G. K. Rattu;Nicolas Chamberlain;Jonathon M Cahoon;K. Lahue;N. Daphtary;M. Aliyeva;David G. Chapman;Dhimant H Desai;M. Poynter;V. Anathy
内质网（ER）应激诱导的未折叠蛋白反应在炎症性疾病（包括过敏性气道疾病）中起着关键作用。然而，抑制ER应激在治疗过敏性气道疾病中的益处还不为人所知。在此，我们测试了化学伴侣，牛磺熊去氧胆酸（TUDCA），在对抗过敏性哮喘的治疗潜力，使用小鼠模型的屋尘螨（HDM）诱导的过敏性气道疾病。在HDM激发阶段（预防方案）、HDM激发阶段后（治疗方案）或在随后的HDM再激发期间（再激发方案）进行TUDCA给药。在预防方案中，TUDCA显著降低了HDM诱导的炎症、ER应激标志物、气道高反应性（AHR）和纤维化。同样，在治疗方案中，TUDCA给药有效降低了HDM诱导的气道炎症、粘液化生、ER应激标志物和AHR，但不降低气道重塑。有趣的是，在HDM再激发方案中治疗性给予TUDCA显著减弱了HDM诱导的气道炎症、粘液化生、ER应激标志物、乙酰甲胆碱诱导的AHR和气道纤维化重塑。这些结果表明，通过施用化学伴侣抑制肺中的ER应激可能是治疗过敏性气道疾病的有价值的策略。
Endoplasmic reticulum (ER) stress-induced unfolded protein response plays a critical role in inflammatory diseases, including allergic airway disease. However, the benefits of inhibiting ER stress in the treatment of allergic airway disease are not well known. Herein, we tested the therapeutic potential of a chemical chaperone, tauroursodeoxycholic acid (TUDCA), in combating allergic asthma, using a mouse model of house dust mite (HDM)-induced allergic airway disease. TUDCA was administered during the HDM-challenge phase (preventive regimen), after the HDM-challenge phase (therapeutic regimen), or therapeutically during a subsequent HDM rechallenge (rechallenge regimen). In the preventive regimen, TUDCA significantly decreased HDM-induced inflammation, markers of ER stress, airway hyperresponsiveness (AHR), and fibrosis. Similarly, in the therapeutic regimen, TUDCA administration efficiently decreased HDM-induced airway inflammation, mucus metaplasia, ER stress markers, and AHR, but not airway remodeling. Interestingly, TUDCA administered therapeutically in the HDM rechallenge regimen markedly attenuated HDM-induced airway inflammation, mucus metaplasia, ER stress markers, methacholine-induced AHR, and airway fibrotic remodeling. These results indicate that the inhibition of ER stress in the lungs through the administration of chemical chaperones could be a valuable strategy in the treatment of allergic airway diseases.