Stress in the ER (endoplasmic reticulum): a matter of life and death for epithelial cells.
Stress in the ER (endoplasmic reticulum): a matter of life and death for epithelial cells.
复制标题
ER（内质网）中的压力：事关上皮细胞的生死。
DOI：
10.1164/rccm.200807-1138ed
复制
发表时间：
2008
影响因子：
24.7
通讯作者：
Limper,AndrewH
中科院分区：
文献类型：
--
作者：
Horowitz,JeffreyC;Limper,AndrewH
Idiopathic pulmonary fibrosis (IPF) is believed to result from aberrant repair of chronic or recurrent alveolar epithelial injury (1). Fibroblastic foci, aggregates of myofibroblasts that underlie injured epithelial cells, are the prevailing ‘‘active’’lesions of fibrosis (2). Alveolar epithelial cells overlying fibroblastic foci show evidence of a regenerative response to injury, with hyperplasia and proliferation, as well as evidence of apoptosis (3). In animal models, alveolar epithelial cell apoptosis is sufficient to induce fibrogenesis, whereas blockade of epithelial apoptosis can attenuate fibrosis (4, 5). The mechanisms of alveolar epithelial cell apoptosis in IPF have not been defined. Apoptosis is a critical component of tissue homeostasis and wound repair (6, 7). Recent studies have defined alternative forms of programmed cell death, such as autophagy, which overlap with apoptosis and share the apoptotic machinery (7, 8). Endoplasmic reticulum (ER) stress has been identified as a stimulus of programmed cell death through both classic apoptosis and autophagic pathways (9). Stimuli such as nutrient deprivation, hypoxia, oxidative stress, and defective protein secretion induce ER stress, leading to impaired post-translational processing of secretory proteins, which accumulate within the cell (10). This triggers a cytoprotective ‘‘unfolded protein response’’that decreases global protein synthesis while increasing production of cellular chaperones and other mediators of protein folding and secretion (10). If the unfolded protein response fails to control the cytotoxic effect of these accumulated proteins, cells will commit to a pathway of regulated cell death (11). Accordingly, chronic ER stress is implicated in the pathogenesis of several chronic diseases, including amyloidosis, Alzheimer’s disease, and diabetes. Until recently ER stress had not been investigated in the context of chronic lung disease. In this issue of the Journal (pp. 838–846), Korfei and colleagues provide information regarding ER stress in the pathogenesis of IPF (12). The major finding of this study is the strong association between ER stress and type II alveolar epithelial cell apoptosis in IPF. Importantly, this study examined tissue and primary cells from patients with sporadic IPF and compared them with tissue from patients with chronic obstructive pulmonary disease (COPD) or with tissue and cells from normal lungs. The findings demonstrate that epithelial cells from both IPF and COPD lungs are undergoing apoptosis, as evidenced by caspase-3 activation and Bax dimerization. The IPF specimens also show activation of ER stress responses mediated by activating transcription factor (ATF)-4, ATF-6, and CAAT/enhancer binding protein homologous protein (CHOP)(10). The COPD specimens, in contrast, reveal that type II cell apoptosis occurs in the absence of ER stress. Through evaluation of primary epithelial cells from IPF and normal lungs, the authors further demonstrate that ER stress markers colocalize with the type II epithelial cell markers surfactant protein (SP)-B, SP-C, and thyroid transcription factor-1 (TTF-1) in the IPF specimens, but not in the COPD or normal specimens.Although this study confirms the association between ER stress and type II cell apoptosis in IPF, it does not address the mechanisms triggering ER stress. Lawson and colleagues recently reported similar findings of ER stress in the epithelium of patients with sporadic and familial IPF (13). Within the familial IPF subpopulation, evidence of ER stress was observed in patients with and without mutations in SP-C (14). The finding of ER stress in sporadic and non–SP-C familial IPF demonstrates that a variety of mechanisms apart from failure …
