Nature Medicine 15, 1077 - 1081(2009)
Published online: 23 August 2009 | doi:10.1038/nm.2005

NADPH oxidase-4 mediates myofibroblastactivation and fibrogenic responses to lung injury

NADPH氧化酶-4介导肌成纤维细胞活化和对肺损伤的纤

NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lu.pdf

Louise Hecker^1,4, Ragini Vittal^1,4, Tamara Jones¹, Rajesh Jagirdar¹, Tracy RLuckhardt¹, Jeffrey CHorowitz¹, SubramaniamPennathur², Fernando JMartinez¹ & Victor JThannickal^1,3

Abstract

Members of the NADPH oxidase (NOX) family ofenzymes, which catalyze the reduction of O₂ to reactive oxygenspecies, have increased in number during eukaryotic evolution^{1, 2}. Seven isoformsof the NOXgene family havebeen identified in mammals; however, specific roles of NOX enzymes in mammalianphysiology and pathophysiology have not been fully elucidated^{3, 4}. The bestestablished physiological role of NOX enzymes is in host defense againstpathogen invasion in diverse species, including plants^{5, 6}. The prototypicalmember of this family, NOX-2 (gp91^phox), is expressed inphagocytic cells and mediates microbicidal activities^{7, 8}. Here we report arole for the NOX4 isoform in tissuerepair functions of myofibroblasts and fibrogenesis. Transforming growthfactor-1 (TGF-1) induces NOX-4expression in lung mesenchymal cells via SMAD-3, a receptor-regulated proteinthat modulates gene transcription. NOX-4–dependent generation of hydrogenperoxide (H₂O₂) is required for TGF-1–inducedmyofibroblast differentiation, extracellular matrix (ECM) production andcontractility. NOX-4 is upregulated in lungs of mice subjected to noninfectiousinjury and in cases of human idiopathic pulmonary fibrosis (IPF). Genetic orpharmacologic targeting of NOX-4 abrogates fibrogenesis in two murine models oflung injury. These studies support a function for NOX4 in tissuefibrogenesis and provide proof of concept for therapeutic targeting of NOX-4 inrecalcitrant fibrotic disorders.

NADPH氧化酶（NOX）家族的成员，其催化将O ²还原成活性氧，在真核生物进化期间数量增加^1,2。在哺乳动物中，已经鉴定了NOX基因家族的7个不同亚型，然而，NOX酶在哺乳动物生理学和病理生理学中的具体作用尚未完全阐明，NOX酶目前能够确定的生理作用是宿主防御不同物种的病原体入侵，其中也包括植物。例如，该家族的原型成员，NOX-2（gp91phox），在吞噬细胞中表达并介导杀灭微生物活性。在这篇文献中，作者报告了NOX4在肌成纤维细胞和纤维发生的组织修复功能中的作用。转化生长因子-1（TGF-1）通过SMAD-3（一种调节基因转录的受体调节蛋白）诱导肺间充质细胞中的NOX-4表达。TGF-1诱导的肌成纤维细胞分化、细胞外基质（ECM）生产和收缩性需要NOX-4依赖性产生过氧化氢（H₂O₂）。NOX-4在受到非感染性损伤的小鼠的肺中以及在特发性肺纤维化（IPF）的情况下上调。在两种小鼠肺损伤模型中，NOX-4的遗传或药理学靶向敲除抑制了纤维化过程。这些研究表明，组织纤维化过程中NOX4可能发挥重要功能，并提示，在顽固性纤维化疾病中，靶向NOX-4干预可能具有重要的临床价值。