NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
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DOI：
10.1183/13993003.01949-2019
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发表时间：
2021-01-01
影响因子：
24.3
通讯作者：
Dupuy, Corinne
中科院分区：
文献类型：
--
作者：
Louzada, Ruy Andrade;Corre, Raphael;Dupuy, Corinne
间质性肺成纤维细胞活化与细胞外基质的产生是肺纤维化的病理特征，并受转化生长因子(TGF)- β 1/Smad信号的调控。tgf - β 1和氧化应激共同驱动纤维化。细胞可以通过激活和/或诱导NADPH氧化酶产生活性氧，如双氧化酶（DUOX1/2）。由于在不同的实验模型中，DUOX酶作为细胞外过氧化氢（H2O2）生成系统参与细胞外基质形成和伤口愈合，我们假设基于DUOX的NADPH氧化酶在肺纤维化的病理生理中发挥作用。我们的体内数据（特发性肺纤维化患者和肺纤维化小鼠模型）表明，NADPH氧化酶DUOX1在肺损伤的反应中被诱导。DUOX1缺陷小鼠（DUOX1（+/-）和DUOX1(-/-)）的纤维化表型减弱。除了在气道上皮表面高表达外，DUOX1似乎在重塑肺的成纤维细胞病灶中表达良好。通过使用原代人和小鼠肺成纤维细胞，我们发现tgf - β 1上调DUOX1及其成熟因子DUOXA1，并且DUOX1衍生的H2O2通过阻止phospho-Smad3降解而延长了tgf - β 1激活的Smad3磷酸化的持续时间。机制分析表明，DUOX1抑制phospho-Smad3与泛素连接酶NEDD4L的相互作用，阻止NEDD4L介导的phospho-Smad3泛素化及其靶向降解。这些发现强调了DUOX1衍生的H2O2在正反馈中的作用，该正反馈放大了tgf - β 1通路的信号输出，并确定了DUOX1作为肺纤维化的新治疗靶点。
Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-beta 1/Smad signalling. TGF-beta 1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (H2O2)-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.Our in vivo data (idiopathic pulmonary fibrosis patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1(+/-) and DUOX1(-/-)) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-beta 1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2 promoted the duration of TGF-beta 1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.These findings highlight a role for DUOX1-derived H2O2 in a positive feedback that amplifies the signalling output of the TGF-beta 1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.