Proteostasis: a new therapeutic paradigm for pulmonary disease.
Proteostasis: a new therapeutic paradigm for pulmonary disease.
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DOI：
10.1513/pats.201008-055ms
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发表时间：
2011-05-01
期刊：
影响因子：
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通讯作者：
Balch, William E
中科院分区：
文献类型：
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作者：
Bouchecareilh, Marion;Balch, William E
在肺部病理中，α 1AT、慢性阻塞性肺病（COPD）、肺气肿和哮喘是由气道中的局部环境应激触发的疾病，我们在本文中将其统称为气道应激疾病（ASD）。α-1-抗胰蛋白酶（alpha 1AT）缺乏症是一种遗传性遗传疾病，是肝细胞中蛋白质合成期间alpha 1AT错误折叠的结果，减少了向血浆的分泌和向肺的递送。肺中α 1AT的缺乏引发了与其他ASD相似的病理表型。此外，肺中alpha 1AT的损失是COPD/肺气肿的众所周知的环境风险因素。到目前为止，还没有有效的治疗方法来解决ASD，这反映了对其细胞基础的普遍缺乏了解。在此，我们提出ASD是蛋白稳态紊乱。也就是说，它们由共同的主题启动和传播-对由蛋白质稳定网络（PN）维持的蛋白质折叠能力的挑战（参见Balch等人，Science 2008;319：916-919）。PN是分子伴侣和降解组分的网络，其产生并管理负责正常人体生理学的蛋白质折叠途径。在ASD中，我们认为PN系统未能对由于遗传和环境压力而增加的未折叠蛋白质负担作出反应，从而触发肺病理生理学。我们引入了蛋白质稳态调节剂（PR）的启用概念，这些调节信号通路的小分子控制PN组分的组成和活性，作为ASD治疗管理的新的和通用的方法。
Among lung pathologies, alpha1AT, chronic obstructive pulmonary disease (COPD), emphysema, and asthma are diseases triggered by local environmental stress in the airway that we refer to herein collectively as airway stress diseases (ASDs). A deficiency of alpha-1-antitrypsin (alpha1AT) is an inherited genetic disorder that is a consequence of the misfolding of alpha1AT during protein synthesis in liver hepatocytes, reducing secretion to the plasma and delivery to the lung. Deficiency of alpha1AT in the lung triggers a similar pathological phenotype to other ASDs. Moreover, the loss of alpha1AT in the lung is a well-known environmental risk factor for COPD/emphysema. To date there are no effective therapeutic approaches to address ASDs, which reflects a general lack of understanding of their cellular basis. Herein, we propose that ASDs are disorders of proteostasis. That is, they are initiated and propagated by a common theme-a challenge to protein folding capacity maintained by the proteostasis network (PN) (see Balch et al., Science 2008;319:916-919). The PN is a network of chaperones and degradative components that generates and manages protein folding pathways responsible for normal human physiology. In ASD, we suggest that the PN system fails to respond to the increased burden of unfolded proteins due to genetic and environmental stresses, thus triggering pulmonary pathophysiology. We introduce the enabling concept of proteostasis regulators (PRs), small molecules that regulate signaling pathways that control the composition and activity of PN components, as a new and general approach for therapeutic management of ASDs.