Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Veterans Affairs Medical Center, Nashville, Tennessee, USA.
J Clin Invest. 2018 Jan 2;128(1):64-73. doi: 10.1172/JCI93560.
Eukaryotic cells contain an elegant protein quality control system that is crucial in maintaining cellular homeostasis; however, dysfunction of this system results in endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Severe or prolonged ER stress is associated with the development of degenerative and fibrotic disorders in multiple organs, as evidenced by the identification of disease-causing mutations in epithelial-restricted genes that lead to protein misfolding or mistrafficking in familial fibrotic diseases. Emerging evidence implicates ER stress and UPR signaling in a variety of profibrotic mechanisms in individual cell types. In epithelial cells, ER stress can induce apoptosis, inflammatory signaling, and epithelial-mesenchymal transition. In other cell types, ER stress is linked to myofibroblast activation, macrophage polarization, and T cell differentiation. ER stress-targeted therapies have begun to emerge using approaches that range from global enhancement of chaperone function to selective targeting of activated ER stress sensors and other downstream mediators. As the complex regulatory mechanisms of this system are further clarified, there are opportunities to develop new disease-modifying therapeutic strategies in a wide range of chronic fibrotic diseases.
真核细胞含有一个精致的蛋白质质量控制系统，对于维持细胞内稳态至关重要；然而，该系统的功能障碍会导致内质网（ER）应激和未折叠蛋白反应（UPR）的激活。严重或长期的 ER 应激与多种器官中退行性和纤维性疾病的发展有关，这可以从导致家族性纤维性疾病中蛋白质错误折叠或运输错误的上皮细胞特异性基因的致病突变的鉴定中得到证明。新出现的证据表明 ER 应激和 UPR 信号在个体细胞类型中的多种促纤维化机制中起作用。在上皮细胞中，ER 应激可诱导细胞凋亡、炎症信号和上皮-间充质转化。在其他细胞类型中，ER 应激与肌成纤维细胞激活、巨噬细胞极化和 T 细胞分化有关。已经开始出现针对 ER 应激的靶向治疗方法，范围从全局增强伴侣蛋白功能到选择性靶向激活的 ER 应激传感器和其他下游介质。随着该系统复杂调节机制的进一步阐明，有机会在广泛的慢性纤维性疾病中开发新的疾病修饰治疗策略。
