Department of Infection, Immunity and Cardiovascular Diseases, The University of Sheffield, Sheffield, UK.
Medicine, University of Cambridge, Cambridge, UK.
Thorax. 2021 Jan;76(1):92-99. doi: 10.1136/thoraxjnl-2019-213738. Epub 2020 Oct 19.
The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.
肺部暴露于一系列环境毒素（包括香烟烟雾、空气污染、石棉）和病原体（细菌、病毒和真菌）中，大多数呼吸系统疾病都与局部或全身缺氧有关。所有这些不利因素都可能引发内质网（ER）应激。ER 是细胞内合成分泌蛋白和膜蛋白的关键部位，调节其折叠、组装成复合物、运输和降解。腔内错误折叠蛋白的积累会导致 ER 应激，从而激活未折叠蛋白反应（UPR）。UPR 的效应物暂时减少蛋白质合成，同时增强错误折叠蛋白的降解并增加 ER 的折叠能力。如果成功，内稳态得到恢复，蛋白质合成恢复，但如果 ER 应激持续存在，细胞死亡途径被激活。内质网应激和由此产生的 UPR 发生在一系列肺部损伤中，其结果在许多呼吸系统疾病中起着重要作用。UPR 在几种呼吸系统疾病患者的气道中以及相应的实验模型中被触发。内质网应激已被牵连到肺纤维化的起始和进展中，越来越多的证据表明，内质网应激发生在阻塞性肺疾病（特别是哮喘）、肺部感染（一些病毒感染和囊性纤维化气道）和肺癌中。虽然已经使用了一些小分子抑制剂来研究 UPR 在疾病模型中的作用，但其中许多工具具有复杂的非靶向作用，因此可能需要额外的证据（例如，来自遗传操作）来支持基于这些药物制剂的影响的结论。UPR 的异常激活可能与疾病的发病机制和进展有关，但目前，我们对内质网应激与这些过程相关的特定疾病机制的理解还不完整。尽管如此，UPR 抵抗内质网应激并影响一系列呼吸系统疾病的能力正变得越来越明显，因此 UPR 作为治疗干预策略的潜在目标引起了人们的关注。
