Introduction The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. Methods Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. Results Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone ( BiP, CANX, CALR ), ER-associated protein degradation ( EDEM1, DERL1) and ER stress-induced apoptosis ( DDIT3, PPP1R15A ) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. Conclusion Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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内质网未折叠蛋白反应信号在严重嗜酸性和中性粒细胞哮喘中发生改变

简介 内质网 (ER) 应激在哮喘中的意义尚不清楚。在这里，我们证明 ER 应激和未折叠蛋白反应 (UPR) 与疾病严重程度和炎症表型有关。方法 诱导痰液 (n=47)、支气管灌洗液 (n=23) 和支气管内活检 (n=40) 从具有不同疾病严重程度、炎症表型的哮喘患者和健康对照中收集。评估了 ER 应激和 UPR 的标志物。这些标志物也在已建立的嗜酸性和中性粒细胞哮喘小鼠模型中进行了评估。结果 我们的结果表明哮喘中 ER 应激和 UPR 通路增加，这些与临床严重程度和炎症表型有关。与 ER 蛋白伴侣相关的基因（BiP、CANX、CALR）、ER 相关蛋白降解（EDEM1、在哮喘参与者中，DERL1) 和 ER 应激诱导的细胞凋亡 (DDIT3, PPP1R15A) 失调，并与肺功能受损（1 秒内用力呼气量）和活动性嗜酸性粒细胞和中性粒细胞炎症有关。ER应激基因也显示出与经典Th2（白细胞介素4、IL-4/13）基因、Th17（IL-17F/CXCL1）基因、促炎（IL-1b、肿瘤坏死因子α、IL-8）基因显着相关和哮喘参与者痰液中的炎症小体激活 (NLRP3)。患有过敏性气道疾病 (AAD) 和严重类固醇不敏感 AAD 的小鼠也表现出肺部 ER 应激信号增加。结论 升高的 ER 应激与哮喘中严重的嗜酸性和中性粒细胞炎症有关，可能在哮喘的发病机制中起关键作用。