TNFGAMMA EFFECTS ON BLOOD BRAIN BARRIER PERMEABILITY

TNFγ 对血脑屏障通透性的影响

• 批准号: 6393591
• 负责人: DONALD W MILLER
• 金额: $ 10.04万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393591
• 关键词: actins; animal tissue; arachidonate; bacterial toxins; blood brain barrier; brain metabolism; cardiovascular pharmacology; cerebral cortex; cerebrovascular occlusions; cyclic AMP; cyclic GMP; guanine nucleotide binding protein; laboratory rat; membrane permeability; microdialysis; neuropharmacology; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium permeability

DESCRIPTION: (Adapted from Applicant's Abstract): Tumor necrosis factor-alpha (TNF-a) is a cytokine released in response to inflammatory events in the body. The increased levels of TNF-a in the central nervous system observed in conditions such as multiple sclerosis, bacterial meningitis, viral infections and brain ischemia suggest that the cytokine may be involved in the pathogenesis of these diseases. A major cellular target for TNF-a is the endothelium, where increases in coagulant activity, cell adhesiveness and vascular permeability are observed. Indeed, exogenous administration of TNF-a produces significant increases in blood-brain barrier (BBB) permeability. Therefore, understanding the mechanisms through which TNF-a produces changes in the permeability of brain microvessel endothelial cells that form the BBB, may provide insight into the cause and effective treatment of inflammatory events within the central nervous system. The proposed studies will examine the effects of TNF-a on BBB permeability on two distinct levels. First, primary cultured bovine brain microvessel endothelial cells (BBMEC) will be used as an in vitro model of the BBB to examine the cellular factors involved in the permeability effects of TNF-a. The hypothesis to be examined is that inhibition of actin stress filament formation in the cells will prevent increases in BBMEC monolayer permeability observed with TNF-a. The specific aims for the in vitro studies will be to evaluate the effects that 1) inhibition of Rho-mediated GTP binding proteins, 2) alterations in cyclic nucleotide signaling pathways, and 3) inhibition of arachidonic acid metabolism has on TNF-alpha-induced changes in actin filament formation and BBMEC monolayer permeability. Secondly, the effects of TNF-a on BBB will be evaluated in vivo. The hypothesis for the in vivo studies is that changes in BBB permeability observed under inflammatory conditions in the brain are directly correlated to the amount of TNF-a released. For these studies, microdialysis probes will be implanted into the cortex of rats. The specific aims for the in vivo portion of the proposal are to 1) determine the dose-response relationship between cortically administered TNF-a and increases in BBB permeability, and 2) correlate the endogenous release of TNF-a following cortical injection of bacterial toxin or cerebral blood flow occlusion with changes in BBB permeability. Microdialysis probes will be used to deliver exogenous TNF-a to specific sites in the cortex as well as sampling endogenously released TNF-a. Together, the proposed studies will provide a better understanding of the mechanisms involved in TNF-a effects on BBB permeability.

描述：（改编自申请人的摘要）：肿瘤坏死 因子-Alpha（TNF-A）是释放的细胞因子，以应对炎症 体内的事件。 中枢神经中TNF-A的水平增加 在多发性硬化症，细菌等条件下观察到的系统 脑膜炎，病毒感染和脑缺血表明细胞因子 可能参与这些疾病的发病机理。 主要的细胞 TNF-A的靶标是内皮，其中凝血活性增加， 观察到细胞粘附性和血管通透性。 确实，外源 TNF-A给药可显着增加血脑 屏障（BBB）渗透率。 因此，通过理解机制 TNF-A产生大脑微血管的渗透性的变化 形成BBB的内皮细胞可能会洞悉原因和 有效治疗中枢神经内的炎症事件 系统。 拟议的研究将检查TNF-A对BBB的影响 两个不同级别的渗透性。 首先，主要培养的牛大脑 微血管内皮细胞（BBMEC）将用作体外模型 BBB检查涉及渗透率效应的细胞因子 tnf-a。 要研究的假设是抑制肌动蛋白胁迫 细胞中的细丝形成将防止BBMEC单层增加 用TNF-A观察到渗透性。 体外的具体目的 研究将是评估1）抑制Rho介导的影响 GTP结合蛋白，2）环状核苷酸信号转导的改变 途径和3）抑制花生四烯酸代谢对 TNFα诱导的肌动蛋白丝形成和BBMEC单层变化 渗透性。 其次，将评估TNF-A对BBB的影响 体内。 体内研究的假设是BBB的变化 在大脑炎症条件下观察到的渗透性是 与释放的TNF-A的量直接相关。 对于这些研究， 微透析探针将植入大鼠的皮质中。 这 提案的体内部分的具体目的是1）确定 皮质施用的TNF-A和 BBB渗透率的增加，2）将内源性释放相关 皮质注射细菌毒素或脑血流后TNF-A 闭塞随BBB渗透性的变化。 微透析探针将是 用于将外源性TNF-A传递到皮质的特定位点以及 内源释放的TNF-A采样。 拟议的研究一起将 更好地了解TNF-A效应所涉及的机制 关于BBB渗透性。

项目成果

Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells.

肿瘤坏死因子-α 诱导脑微血管内皮细胞中环氧合酶 2 表达和前列腺素释放。

• 发表时间: 2001
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Mark,KS;Trickler,WJ;Miller,DW
• 通讯作者: Miller,DW

Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever.

暴露于三种独特形式的抗真菌药物两性霉素 B 后，牛脑内皮细胞中前列腺素 E-2 的释放：COX-2 在两性霉素 B 诱导发热中的作用。

• DOI: 10.1016/s0024-3205(03)00172-3
• 发表时间: 2003
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: McGuire,TimothyR;Trickler,WilliamJ;Hock,Lynette;Vrana,Amy;Hoie,EricB;Miller,DonaldW
• 通讯作者: Miller,DonaldW

Release of TNF-alpha and IL-1beta from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin.

猪脑内皮细胞释放的 TNF-α 和 IL-1β 与三种市售两性霉素制剂的致热潜力相对应。

• DOI: 10.1007/s00011-005-1370-9
• 发表时间: 2005
• 期刊: Inflammation research : official journal of the European Histamine Research Society ... [et al.].
• 作者: McGuire,TR;Trickler,WJ;Smith,L;Hoie,EB;Miller,DW
• 通讯作者: Miller,DW

In vitro and in vivo models for assessing drug efflux transporter activity.

用于评估药物流出转运蛋白活性的体外和体内模型。

• DOI: 10.1016/s0169-409x(02)00170-9
• 发表时间: 2003
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Zhang,Yan;Bachmeier,Corbin;Miller,DonaldW
• 通讯作者: Miller,DonaldW