LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

白三烯和血脑屏障

• 批准号: 6217917
• 负责人: Keith L. Black
• 金额: $ 16.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217917
• 关键词: acivicin; astrocytes; autoradiography; blood brain barrier; bradykinin; brain edema; brain neoplasms; capillary; cytokine receptors; eicosanoid metabolism; glioma; histamine; human tissue; in situ hybridization; laboratory rat; leukotrienes; lipoxygenase; peptidyl dipeptidase; protein glutamine gamma glutamyltransferase; receptor binding; vascular endothelium permeability

There is a correlation between LTC4 in human brain tumors and the amount of edema surrounding tumors. Human brain tumors express arachidonate 5- lipoxygenase mRNA and the inhibition of 5-lipoxygenase will decrease blood-brain barrier (BBB) permeability in tumors. Leukotriene (LT) C4 will selectively open the blood-tumor barrier (BTB) in tumors two-fold without increasing permeability in the normal brain. On the basis of these findings we have suggested that leukotrienes could allow for increased delivery of anti-tumor drugs to tumor tissue. Conversely, inhibition of 5-lipoxygenase could reduce brain tumor edema. To investigate further leukotrienes and the concept of an enzymatic BBB: 1A) in rats with brain tumors, changes in cerebral blood flow and blood volume after intracarotid (IC) leukotriene infusions will be quantitated; and 1B) electron microscopy will be used to determine whether the mechanism by which LT's increase BBB permeability, is by opening tight junctions or increasing pinocytic transport. 2A) To identify another possible enzyme in the "enzymatic barrier," antiserum to dipeptidase (the enzyme that converts LTD4 to LTE4) is used to determine whether dipeptidase is present in rat and human brain capillaries, and if so, whether it is lost in brain tumors or ischemia. 2B) The dose response to gamma glutamyl transpeptidase (gGTP) inhibition by acivicin to LTC4 opening will be determined. To further understand the "enzymatic barrier," 3A) other vasoactive compounds, bradykinin and histamine, that may also allow selective BBB opening will be infused IC alone and in combination with leukotrienes, with and without histamine H1 and H2 receptor blockers and 5-lipoxygenase inhibitors. 3B) The effect of these compounds on cerebral blood volume will be determined. 3C) Electron microscopy will also be utilized to determine the mechanism of increased permeability. 3D) Opening of the BBB to different size molecules by these compounds will be determined. 4) 5-lipoxygenase transcripts will be further characterized in human brain tumors. 5) Studies will determine whether permeability to drugs is increased in experimental tumors after intracarotid infusion of leukotrienes and other vasoactive compounds.

人脑肿瘤中的LTC4与数量之间存在相关性 周围肿瘤的水肿。 人脑肿瘤表达蛛网膜5- 脂氧合酶mRNA和5-脂蛋白酶的抑制作用将减少 肿瘤中的血脑屏障（BBB）渗透性。 白细胞（LT）C4 将有选择地打开两倍的肿瘤中的血肿瘤屏障（BTB） 不增加正常大脑的渗透性。 基于 这些发现我们建议白细胞可以允许 增加抗肿瘤药物向肿瘤组织的递送。 反过来， 抑制5-脂氧酶可以减少脑肿瘤水肿。 到 研究进一步的白细胞和酶促BBB的概念：1a） 在患有脑肿瘤的大鼠中，脑血流和血液的变化 核内（IC）白细胞输注后的体积将被定量； 和1b）电子显微镜将用于确定是否是否 LT提高BBB渗透性的机制是通过紧密打开 连接或增加皮细胞转运。 2a）确定另一个 在“酶屏障”中可能的酶，抗二肽酶的抗血清（ 将LTD4转换为LTE4的酶用于确定是否是否 二肽酶存在于大鼠和人脑毛细血管中，如果是的， 无论是在脑肿瘤还是缺血中丢失。 2b）剂量反应 Acivicin抑制LTC4的γ谷氨酰基转肽酶（GGTP） 开放将确定。 进一步理解“酶促的 障碍物，“ 3a）其他血管活性化合物，缓激肽和组胺， 可能还允许选择性的BBB开放单独注入IC和 与白细胞结合，有和没有组胺H1和H2 受体阻滞剂和5-脂氧合酶抑制剂。 3b）这些效果 将确定脑血容量上的化合物。 3c）电子 显微镜还将用于确定增加的机制 渗透性。 3D）将BBB开放至不同大小的分子 将确定化合物。 4）5-脂氧合酶的转录本将是 在人脑肿瘤中进一步特征。 5）研究将确定 在实验肿瘤中，对药物的渗透性是否增加 白细胞和其他血管活性化合物的核内输注。