NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
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DOI：
10.1093/brain/aws012
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Lassmann H
中科院分区：
文献类型：
--
作者：
Fischer MT;Sharma R;Lim JL;Haider L;Frischer JM;Drexhage J;Mahad D;Bradl M;van Horssen J;Lassmann H
多发性硬化症是一种中枢神经系统的慢性炎症性疾病，与脱髓鞘和神经变性有关。组织损伤的机制尚不清楚，但最近的数据表明，线粒体损伤可能在这一过程中起重要作用。活性氧和一氧化氮可以触发线粒体损伤，我们最近提供了证据，证明在活动性多发性硬化症病变的早期阶段，少突胶质细胞和营养不良轴突的氧化损伤。在这项研究中，我们通过仔细分期和解剖病变区域的基因表达以及免疫组织化学分析蛋白质表达来确定活性氧和氮的潜在来源。全基因组微阵列证实了活动性多发性硬化症病变中的线粒体损伤，这可能是活性氧的重要来源。此外，我们发现各种烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基的基因表达水平在初始多发性硬化症病变和对照白质之间存在差异。这些结果通过免疫组化在蛋白水平上得到证实，在经典活性和缓慢扩张病变中，激活的小胶质细胞中gp91phox、p22phox、p47phox、烟酰胺腺嘌呤二核苷酸磷酸氧化酶1和烟酰胺腺嘌呤二核苷酸磷酸氧化酶组织者1亚基上调。gp91phox和p22phox亚基在小胶质细胞中组成性表达，并在初始病变中上调。相比之下，p47phox、烟酰胺腺嘌呤二核苷酸磷酸氧化酶1和烟酰胺腺嘌呤二核苷酸磷酸氧化酶组织者1的表达更局限于初始损伤区或急性或早期复发/缓解型多发性硬化症患者的病变。双标记显示烟酰胺腺嘌呤二核苷酸磷酸氧化酶亚基在活化的小胶质细胞和浸润的巨噬细胞中共表达，提示功能复合物的组装。我们的数据表明，激活的小胶质细胞和巨噬细胞中炎症相关的氧化爆发在多发性硬化症发病过程中脱髓鞘和自由基介导的组织损伤中起重要作用。
Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions. In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression. Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species. In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter. These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions. The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion. In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis. Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and infiltrated macrophages, suggesting the assembly of functional complexes. Our data suggest that the inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in demyelination and free radical-mediated tissue injury in the pathogenesis of multiple sclerosis.
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DOI：
10.1073/pnas.0502552102
发表时间：
2005-07-12
影响因子：
11.1
作者：
Li, JR;Baud, O;Rosenberg, PA
通讯作者：
Rosenberg, PA
影响因子：
12.7
作者：
Diaz-Sanchez, M;Williams, K;Esiri, MM
通讯作者：
Esiri, MM
影响因子：
6.4
作者：
Gray, Elizabeth;Thomas, Taya L.;Love, Seth
通讯作者：
Love, Seth
影响因子：
11.2
作者：
Bauer, Jan;Eiger, Christian E.;Bien, Christian G.
通讯作者：
Bien, Christian G.
影响因子：
11.2
作者：
Dutta, R;McDonough, J;Trapp, BD
通讯作者：
Trapp, BD