A Key Role for NOX4 in Epithelial Cell Death During Development of Lung Fibrosis
A Key Role for NOX4 in Epithelial Cell Death During Development of Lung Fibrosis
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DOI：
10.1089/ars.2010.3829
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发表时间：
2011-08-01
影响因子：
6.6
通讯作者：
Krause, Karl-Heinz
中科院分区：
文献类型：
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作者：
Carnesecchi, Stephanie;Deffert, Christine;Krause, Karl-Heinz
肺纤维化的发病机制与氧化应激有关，可能由产生NADPH氧化酶NOX 4的活性氧（ROS）产生。上皮细胞死亡是疾病发展的关键早期步骤，随后才进入纤维化阶段。我们证明，在特发性肺纤维化患者的肺中，在增生的肺泡II型细胞中有强烈的NOX 4表达。目的：为了研究NOX 4在肺泡细胞死亡中可能的致病作用，我们已经产生了NOX 4缺陷小鼠。结果如下：博莱霉素给药3周后，野生型（WT）小鼠出现大量纤维化，而NOX 4缺陷小鼠显示出几乎正常的肺组织学，只有很少的Smad 2磷酸化和肌成纤维细胞积累。然而，NOX 4缺乏的保护作用先于纤维化阶段。事实上，在博来霉素后第7天，WT小鼠的肺显示上皮细胞凋亡和炎症的大量增加。在NOX 4缺陷小鼠中，未观察到细胞凋亡增加，而炎症与WT相当。在体外，暴露于转化生长因子-β（1）的NOX 4缺陷原代肺泡上皮细胞不产生ROS，并被保护免于凋亡。用NOX抑制剂进行急性治疗也减弱了转化生长因子β（1）诱导的细胞凋亡。结论：由NOX 4产生的ROS是导致肺纤维化的上皮细胞死亡的关键因素。抗氧化剂。氧化还原信号。15，607-619。
The pathogenesis of pulmonary fibrosis is linked to oxidative stress, possibly generated by the reactive oxygen species (ROS) generating NADPH oxidase NOX4. Epithelial cell death is a crucial early step in the development of the disease, followed only later by the fibrotic stage. We demonstrate that in lungs of patients with idiopathic lung fibrosis, there is strong expression of NOX4 in hyperplastic alveolar type II cells. Aim: To study a possible causative role of NOX4 in the death of alveolar cells, we have generated NOX4-deficient mice. Results: Three weeks after administration of bleomycin, wild-type (WT) mice developed massive fibrosis, whereas NOX4-deficient mice displayed almost normal lung histology, and only little Smad2 phosphorylation and accumulation of myofibroblasts. However, the protective effects of NOX4 deficiency preceded the fibrotic stage. Indeed, at day 7 after bleomycin, lungs of WT mice showed massive increase in epithelial cell apoptosis and inflammation. In NOX4-deficient mice, no increase in apoptosis was observed, whereas inflammation was comparable to WT. In vitro, NOX4-deficient primary alveolar epithelial cells exposed to transforming growth factor-beta(1) did not generate ROS and were protected from apoptosis. Acute treatment with the NOX inhibitors also blunted transforming growth factor-beta(1)-induced apoptosis. Conclusion: ROS generation by NOX4 is a key player in epithelial cell death leading to pulmonary fibrosis. Antioxid. Redox Signal. 15, 607-619.