1 Centre of Excellence for Translational Research in Asthma & Lung Disease; and.
Am J Respir Cell Mol Biol. 2014 May;50(5):923-31. doi: 10.1165/rcmb.2013-0320OC.
Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.
内质网（ER）应激和随之而来的未折叠蛋白反应（UPR）在炎症中很重要，但在哮喘中研究甚少。我们使用一种具有哮喘特征的过敏性气道炎症（AAI）小鼠模型来了解 ER 应激的作用，并探索吸入化学伴侣的潜在治疗效果，化学伴侣是一种可以促进蛋白质折叠和减少 UPR 的小分子。在为期 7 天的每日变应原挑战模型中，每隔一天测量 UPR 标志物。在第一次变应原挑战后 24 小时内，UPR 标志物增加，并在第三次挑战时达到峰值，此时 AAI 尚未完全建立（从第五次挑战开始）。三种化学伴侣——甘油、海藻糖和三甲胺 N-氧化物（TMAO）——最初在变应原挑战期间给药（预防方案）。这些化学伴侣中最有效的 TMAO 和目前正在临床试验中的化学伴侣 4-苯基丁酸，在 AAI 建立后（治疗方案）进一步测试了其潜在的治疗活性。化学伴侣在两种方案中均表现出剂量依赖性地降低 UPR 标志物、气道炎症和重塑。我们的研究结果表明 ER 应激途径在哮喘发病机制中具有早期和重要的作用，并显示出化学伴侣的治疗潜力。
