Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress.
Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress.
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长期氧化应激诱导的实验性支气管肺发育不良的基因表达谱和组织病理学。
DOI：
10.1016/j.freeradbiomed.2003.12.007
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发表时间：
2004
影响因子：
7.4
通讯作者：
Walther,FransJ
中科院分区：
文献类型：
--
作者：
Wagenaar,GerryTM;terHorst,SimoneAJ;vanGastelen,MargôtA;Leijser,LaraM;Mauad,Thais;vanderVelden,PieterA;deHeer,Emile;Hiemstra,PieterS;Poorthuis,BenJHM;Walther,FransJ
氧化应激是支气管肺发育不良(BPD)发病机制中的一个重要因素。BPD是早产儿的一种慢性肺部疾病，其特征是未成熟肺的肺泡和血管发育受阻。我们用DNA微阵列分析技术研究了在发育囊状阶段暴露于长期高氧的早产大鼠肺中的差异基因表达，这与接受新生儿重症监护的早产儿的肺发育非常相似。实时荧光RT-PCR(27个基因)在很大程度上证实了表达谱，并与组织病理学和Western blotting研究的纤维蛋白沉积相一致。氧化应激影响了一系列复杂的基因，涉及炎症、凝血、纤溶、细胞外基质周转、细胞周期、信号转导和肺泡扩大，并至少部分解释了BPD发生时肺部的病理变化。令人兴奋的发现是纤维蛋白沉积的幅度；趋化因子诱导的中性粒细胞趋化因子-1(CINC-1)、单核细胞趋化蛋白-1(MCP-1)、双调节蛋白、纤溶酶原激活物抑制物-1(PAI-1)、分泌性白细胞蛋白酶抑制物(SLPI)、基质金属蛋白酶-12(MMP12)、p21、金属硫蛋白和血红素加氧酶(HO)上调；成纤维细胞生长因子受体-4(FGFR4)和血管内皮生长因子受体-2(Flk-1)下调。这些发现不仅对了解BPD的病理生理学具有重要意义，而且对于开发新的治疗策略也是至关重要的。
Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies.