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Role of NADPH oxidase in radiation-induced brain injury.

机译：NADPH氧化酶在辐射诱发的脑损伤中的作用。

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摘要

Progressive dementia occurs in 20-50% of long-term survivors of brain cancer after treatment with brain irradiation. The need to both understand and minimize the side effects of brain irradiation is exacerbated by the ever-increasing number of patients with brain metastases that require treatment with whole brain irradiation (WBI); ∼200,000 cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. We hypothesize that the pathogenic mechanism underlying radiation-induced brain injury is the activation of NADPH oxidase and the development of a chronic oxidative stress and subsequent inflammation.;For our in vitro studies, we hypothesized that brain irradiation leads to activation of NADPH oxidase. We report that irradiating rat brain microvascular endothelial cells leads to increased (i) intracellular ROS generation, (ii) activation of the transcription factor NFkappaB, (iii) expression of ICAM-1 and PAI-1, and (iv) expression of Nox4, p22phox , and p47phox. Pharmacologic and genetic inhibition of NADPH oxidase blocked the radiation-mediated upregulation of intracellular ROS, activation of NFkappaB, and upregulation of ICAM-1 and PAI-1. These results suggest that activation of NADPH oxidase may play a role in radiation-induced oxidative stress in vitro.;In an attempt to assess the role of NADPH oxidase in an in vivo setting of radiation-induce brain injury, we hypothesized that NADPH oxidase mediates, in part, the radiation-induced oxidative stress and inflammation observed in mice treated with WBI. We report that WBI of wild type mice leads to acute and chronic increases in (i) intracellular ROS generation, (ii) ICAM-1 expression, and (iii) microglial activation. We further hypothesized irradiating the brain of mice genetically deficient for p47phox (p47 phox -/-) would be associated with a reduced oxidative stress/inflammatory response. However, irradiating the brains of p47phox -/- mice leads to exacerbated radiation-induced intracellular ROS generation and increased ICAM-1 expression in the absence of microglial activation. These results suggest that although NADPH oxidase may regulate radiation-induced oxidative stress and inflammation, the precise elucidation of its mechanistic role will require more appropriate conditional knockout models with which NADPH oxidase inactivation can be spatially and temporally controlled.
机译：进行脑照射治疗后，进展性痴呆发生在20-50％的脑癌长期幸存者中。需要全脑照射（WBI）治疗的脑转移患者的数量不断增加，这加深了对理解和最小化脑照射副作用的需求。每年约有200,000癌症患者接受大范围手术或WBI。目前，还没有成功的治疗放射性辐射引起的脑损伤的方法，也没有任何有效的预防措施。我们假设辐射诱发的脑损伤的致病机制是NADPH氧化酶的激活以及慢性氧化应激和随后的炎症的发展。对于我们的体外研究，我们假设脑部辐射导致NADPH氧化酶的激活。我们报告说，辐照大鼠脑微血管内皮细胞会导致（i）细胞内ROS生成增加；（ii）转录因子NFkappaB的激活；（iii）ICAM-1和PAI-1的表达，以及（iv）Nox4的表达， p22phox和p47phox。 NADPH氧化酶的药理和遗传抑制作用阻止了辐射介导的细胞内ROS的上调，NFkappaB的激活以及ICAM-1和PAI-1的上调。这些结果表明，NADPH氧化酶的激活可能在体外辐射诱导的氧化应激中起作用。为了评估NADPH氧化酶在体内辐射诱发脑损伤中的作用，我们假设NADPH氧化酶介导部分是在用WBI治疗的小鼠中观察到的辐射诱导的氧化应激和炎症。我们报道野生型小鼠的WBI导致（i）细胞内ROS生成，（ii）ICAM-1表达和（iii）小胶质细胞活化的急性和慢性增加。我们进一步假设辐照遗传上缺乏p47phox（p47 phox-/-）的小鼠的大脑与减少的氧化应激/炎症反应有关。但是，在没有小胶质细胞活化的情况下，照射p47phox-/-小鼠的大脑会导致放射线诱导的细胞内ROS产生加剧，并增加ICAM-1表达。这些结果表明，尽管NADPH氧化酶可以调节辐射诱导的氧化应激和炎症，但要精确阐明其机械作用，将需要更适当的条件敲除模型，利用该模型可以在空间和时间上控制NADPH氧化酶的失活。

著录项

  • 作者

    Collins-Underwood, Jennifer Racquel.;

  • 作者单位

    Wake Forest University, The Bowman Gray School of Medicine.;

  • 授予单位 Wake Forest University, The Bowman Gray School of Medicine.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 162 p.
  • 总页数 162
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
  • 关键词

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