NOX4/NADPH 氧化酶在特发性肺纤维化患者的肺成纤维细胞中表达增加，并介导 TGFβ1 诱导的成纤维细胞向肌成纤维细胞分化。
NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta1-induced fibroblast differentiation into myofibroblasts.
机构信息
INSERM, Unité 700, Université Paris 7 Denis Diderot, site Bichat, Paris, France.
出版信息
Thorax. 2010 Aug;65(8):733-8. doi: 10.1136/thx.2009.113456.
BACKGROUND
Persistence of myofibroblasts is believed to contribute to the development of fibrosis in idiopathic pulmonary fibrosis (IPF). Transforming growth factor beta1 (TGFbeta1) irreversibly converts fibroblasts into pathological myofibroblasts, which express smooth muscle alpha-actin (alpha-SMA) and produce extracellular matrix proteins, such as procollagen I (alpha1). Reactive oxygen species produced by NADPH oxidases (NOXs) have been shown to regulate cell differentiation. It was hypothesised that NOX could be expressed in parenchymal pulmonary fibroblasts and could mediate TGFbeta1-stimulated conversion of fibroblasts into myofibroblasts.
METHODS
Fibroblasts were cultured from the lung of nine controls and eight patients with IPF. NOX4, alpha-SMA and procollagen I (alpha1) mRNA and protein expression, reactive oxygen species production and Smad2/3 phosphorylation were quantified, in the absence and in the presence of incubation with TGFbeta1. Migration of platelet-derived growth factor (PDGF)-induced fibroblasts was also assessed.
RESULTS
It was found that (1) NOX4 mRNA and protein expression was upregulated in pulmonary fibroblasts from patients with IPF and correlated with mRNA expression of alpha-SMA and procollagen I (alpha1) mRNA; (2) TGFbeta1 upregulated NOX4, alpha-SMA and procollagen I (alpha1) expression in control and IPF fibroblasts; (3) the change in alpha-SMA and procollagen I (alpha1) expression in response to TGFbeta1 was inhibited by antioxidants and by a NOX4 small interfering RNA (siRNA); (4) NOX4 modulated alpha-SMA and procollagen I (alpha1) expression by controlling activation of Smad2/3; and (5) NOX4 modulated PDGF-induced fibroblast migration.
CONCLUSION
NOX4 is critical for modulation of the pulmonary myofibroblast phenotype in IPF, probably by modulating the response to TGFbeta1 and PDGF.
背景
肌成纤维细胞的持续存在被认为有助于特发性肺纤维化（IPF）的纤维化发展。转化生长因子β 1（TGFβ1）不可逆地将成纤维细胞转化为病理性肌成纤维细胞，后者表达平滑肌α-肌动蛋白（α-SMA）并产生细胞外基质蛋白，如前胶原 I（α1）。NADPH 氧化酶（NOX）产生的活性氧被证明可以调节细胞分化。假设 NOX 可以在肺实质成纤维细胞中表达，并可以介导 TGFβ1 刺激的成纤维细胞向肌成纤维细胞的转化。
方法
从 9 名对照者和 8 名 IPF 患者的肺中培养成纤维细胞。在不存在和存在与 TGFβ1 孵育的情况下，定量测定 NOX4、α-SMA 和前胶原 I（α1）mRNA 和蛋白表达、活性氧产生和 Smad2/3 磷酸化。还评估了血小板衍生生长因子（PDGF）诱导的成纤维细胞的迁移。
结果
结果发现：（1）IPF 患者的肺成纤维细胞中 NOX4 mRNA 和蛋白表达上调，并与α-SMA 和前胶原 I（α1）mRNA 的表达相关；（2）TGFβ1 上调了对照和 IPF 成纤维细胞中的 NOX4、α-SMA 和前胶原 I（α1）表达；（3）抗氧化剂和 NOX4 小干扰 RNA（siRNA）抑制了 TGFβ1 对α-SMA 和前胶原 I（α1）表达的变化；（4）NOX4 通过控制 Smad2/3 的激活来调节α-SMA 和前胶原 I（α1）的表达；（5）NOX4 调节 PDGF 诱导的成纤维细胞迁移。
结论
NOX4 对 IPF 中肺肌成纤维细胞表型的调节至关重要，可能通过调节对 TGFβ1 和 PDGF 的反应。
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