Transforming growth factor β suppresses glutamate-cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model.
Transforming growth factor β suppresses glutamate-cysteine ligase gene expression and induces oxidative stress in a lung fibrosis model.
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DOI：
10.1016/j.freeradbiomed.2012.05.016
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发表时间：
2012-08-01
影响因子：
7.4
通讯作者：
Postlethwait, Edward M.
中科院分区：
文献类型：
--
作者：
Liu, Rui-Ming;Vayalil, Praveen Kumar;Ballinger, Carol;Dickinson, Dale A.;Huang, Wen-Tan;Wang, Suqing;Kavanagh, Terrance J.;Matthews, Qiana L.;Postlethwait, Edward M.
关键词：
在纤维化疾病和实验性纤维化模型中，肺中最丰富的细胞内游离巯基和重要的抗氧化剂谷胱甘肽（GSH）的浓度降低。然而，GSH耗竭的潜在机制和生物学意义仍不清楚。转化生长因子β（TGF-β）是最有效和普遍存在的促纤维化细胞因子，并且其表达在几乎所有纤维化疾病中增加。在这项研究中，我们发现，通过鼻内滴注AdTGF-β1223/225（一种表达组成型活性TGF-β1的腺病毒），将小鼠肺中TGF-β 1的表达增加到与肺纤维化疾病中发现的水平相当，抑制谷氨酸半胱氨酸连接酶（GCL）的催化和修饰亚基的表达，GCL是GSH从头合成的限速酶，降低GSH浓度，增加小鼠肺组织蛋白质和脂质过氧化反应。此外，我们发现，增加TGF-β1表达激活JNK和诱导转录激活因子3（ATF 3），参与调控的GCL（GCLC）的催化亚基的转录抑制因子，在小鼠肺。与盐水处理的对照相比，对照病毒（AdDL 70 -3）对这些参数中的任何一个都没有显著影响。与GSH耗竭同时，TGF-β1诱导肺上皮细胞凋亡和强烈的肺纤维化。重要的是，肺GSH水平恢复正常，而纤维化持续至少21天后，TGF-β1滴注。总之，这些数据表明，TGF-β1表达增加可能有助于在肺纤维化疾病中观察到的GSH耗竭，并且GSH耗竭可能是纤维化发展的早期事件，而不是纤维化发展的结果。
The concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, is decreased in the lung in both fibrotic diseases and experimental fibrosis models. The underlying mechanisms and biological significance of GSH depletion, however, remain unclear. Transforming growth factor beta (TGF-β) is the most potent and ubiquitous profibrogenic cytokine and its expression is increased in almost all fibrotic diseases. In this study, we show that increasing TGF-β1 expression in mouse lung to a level comparable to those found in lung fibrotic diseases by intranasal instillation of AdTGF-β1223/225, an adenovirus expressing constitutively active TGF-β1, suppressed the expression of both catalytic and modifier subunits of glutamate cysteine ligase (GCL), the rate-limiting enzyme in de novo GSH synthesis, decreased GSH concentration, and increased protein and lipid peroxidation in mouse lung. Furthermore, we show that increasing TGF-β1 expression activated JNK and induced activating transcription factor 3 (ATF3), a transcriptional repressor involved in the regulation of the catalytic subunit of GCL (GCLC), in mouse lung. Control virus (AdDL70-3) had no significant effect on any of these parameters, compared to saline treated control. Concurrent with GSH depletion, TGF-β1 induced lung epithelial apoptosis and robust pulmonary fibrosis. Importantly, lung GSH levels returned to the normal whereas fibrosis persisted at least 21 days after TGF-β1 instillation. Together, the data suggest that increased TGF-β1 expression may contribute to the GSH depletion observed in pulmonary fibrosis diseases and that GSH depletion may be an early event in, rather than a consequence of, fibrosis development.
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