A model of the aged lung epithelium in idiopathic pulmonary fibrosis.
A model of the aged lung epithelium in idiopathic pulmonary fibrosis.
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DOI：
10.18632/aging.203291
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发表时间：
2021-07-08
期刊：
影响因子：
--
通讯作者：
Romero F
中科院分区：
文献类型：
--
作者：
Shaghaghi H;Cuevas-Mora K;Para R;Tran C;Roque W;Robertson MJ;Rosas IO;Summer R;Romero F
特发性肺纤维化（IPF）是一种与年龄相关的疾病，普遍预后不良，被认为是由肺泡上皮细胞的重复性微损伤引起的。迄今为止，限制我们对IPF理解的一个主要因素是疾病模型的缺乏，特别是可以概括人类疾病中分子属性的完整补充的体外模型。在本研究中，我们旨在开发一种更接近异常IPF肺上皮的模型。通过将小鼠肺泡上皮细胞暴露于重复的低剂量博来霉素，而不是通常的一次性暴露，我们发现了与IPF肺上皮细胞中的变化惊人相似的变化。这包括获得衰老细胞的多种表型和功能特征，以及采用先前描述的线粒体稳态变化，包括氧化还原平衡、能量产生和线粒体未折叠蛋白反应活性的改变。我们还发现了细胞代谢的显著变化，并检测到蛋白质稳态的严重丧失，其特征在于细胞质蛋白质聚集体的积累、伴侣蛋白表达失调和泛素蛋白酶体系统活性降低。总之，我们描述了一种与IPF中的异常肺上皮非常相似的体外模型。我们认为，这种简单而强大的工具可以帮助发现新的生物学机制，并协助开发新的药理学工具来治疗这种疾病。
Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.
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DOI：
10.1083/jcb.201702058
发表时间：
2017-07-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Quirós PM;Prado MA;Zamboni N;D'Amico D;Williams RW;Finley D;Gygi SP;Auwerx J
通讯作者：
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DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
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Passos JF
DOI：
10.1165/rcmb.2019-0051oc
发表时间：
2019-10-01
影响因子：
6.4
作者：
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通讯作者：
Liu, Gang
影响因子：
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作者：
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Selman, Moises