An Inhibitor of NADPH Oxidase-4 Attenuates Established Pulmonary Fibrosis in a Rodent Disease Model
An Inhibitor of NADPH Oxidase-4 Attenuates Established Pulmonary Fibrosis in a Rodent Disease Model
复制标题
DOI：
10.1165/rcmb.2013-0174oc
复制
发表时间：
2014-01-01
影响因子：
6.4
通讯作者：
Jarai, Gabor
中科院分区：
文献类型：
--
作者：
Jarman, Elizabeth R.;Khambata, Valerie S.;Jarai, Gabor
特发性肺纤维化是一种慢性进行性疾病，发病率不断增加，目前尚无有效的治疗方法。与氧化剂-抗氧化剂失衡相关的氧化应激增加被认为有助于疾病进展。NADPH氧化酶（Nox）是肺和心血管系统内活性氧的主要来源。我们证明了Nox 4亚型在IPF患者的肺中以及博来霉素诱导的肺纤维化和血管重塑的啮齿动物模型中上调。Nox 4是组成型活性的，因此增加的表达水平可能有助于疾病病理学。使用小分子Nox 4/Nox 1抑制剂，我们证明靶向Nox 4导致已建立的纤维化反应减弱，细胞外基质组分胶原蛋白1 α 1、胶原蛋白3 α 1和纤连蛋白的基因转录物减少，原则上与肺纤维化和缺氧介导的血管重塑相关的途径组分减少：转化生长因子（TGF）-β 1、纤溶酶原激活物抑制剂-1、缺氧诱导因子和Nox 4。TGF-β 1是一种主要的纤维化介质，负责诱导与疾病病理学相关的促纤维化途径的上调。使用正常的人肺源性原代成纤维细胞，我们证明了使用小分子拮抗剂抑制Nox 4活性减弱了TGF-β 1介导的促纤维化基因表达上调，并抑制了成纤维细胞向肌成纤维细胞的分化，这与平滑肌肌动蛋白的上调和收缩表型的获得有关。这些研究支持靶向Nox 4可能提供减轻肺纤维化的治疗方法的观点。
Idiopathic pulmonary fibrosis is a chronic progressive disease of increasing prevalence for which there is no effective therapy. Increased oxidative stress associated with an oxidant-antioxidant imbalance is thought to contribute to disease progression. NADPH oxidases (Nox) are a primary source of reactive oxygen species within the lung and cardiovascular system. We demonstrate that the Nox4 isoform is up-regulated in the lungs of patients with IPF and in a rodent model of bleomycin-induced pulmonary fibrosis and vascular remodeling. Nox4 is constitutively active, and therefore increased expression levels are likely to contribute to disease pathology. Using a small molecule Nox4/Nox1 inhibitor, we demonstrate that targeting Nox4 results in attenuation of an established fibrotic response, with reductions in gene transcripts for the extracellular matrix components collagen 1 alpha 1, collagen 3 alpha 1, and fibronectin and in principle pathway components associated with pulmonary fibrosis and hypoxia-mediated vascular remodeling: transforming growth factor (TGF)-beta 1, plasminogen activator inhibitor-1, hypoxia-inducible factor, and Nox4. TGF-beta 1 is a principle fibrotic mediator responsible for inducing up-regulation of profibrotic pathways associated with disease pathology. Using normal human lung-derived primary fibroblasts, we demonstrate that inhibition of Nox4 activity using a small molecule antagonist attenuates TGF-beta 1-mediated up-regulation in expression of profibrotic genes and inhibits the differentiation of fibroblast to myofibroblasts, that is associated with up-regulation in smooth muscle actin and acquisition of a contractile phenotype. These studies support the view that targeting Nox4 may provide a therapeutic approach for attenuating pulmonary fibrosis.