LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

人脑肿瘤中的LTC 4与肿瘤组织中的LTC 4含量之间存在相关性。 肿瘤周围的水肿 人脑肿瘤表达花生四烯酸5- 脂氧合酶mRNA的表达和对5-脂氧合酶的抑制作用将降低 血脑屏障（BBB）通透性。 白三烯（LT）C4 将选择性地打开肿瘤中的血液肿瘤屏障（BTB）两倍 而不会增加正常大脑的渗透性。 的基础上 这些研究结果表明，白三烯可以允许 增加抗肿瘤药物向肿瘤组织的递送。 相反地， 抑制5-脂氧合酶可减轻脑肿瘤水肿。 到 进一步研究白三烯和酶促血脑屏障的概念：1A） 在患有脑肿瘤的大鼠中， 将对颈动脉内（IC）输注白三烯后的体积进行定量; 和1B）电子显微镜将用于确定是否 LT增加BBB渗透性机制是通过打开紧密 连接或增加胞饮转运。2A）识别另一个 可能的酶在“酶屏障”，抗血清二肽酶（ 将LTD 4转化为LTE 4的酶）用于确定是否 二肽酶存在于大鼠和人脑毛细血管中，如果是这样， 无论是在脑肿瘤还是缺血中丢失。2B）剂量响应 阿西维星对LTC 4的γ谷氨酰转肽酶（gGTP）抑制 开幕式将确定。 为了进一步了解“酶” 屏障，”3A）其他血管活性化合物，缓激肽和组胺， 也可以允许选择性地打开BBB，将单独注入IC， 与白三烯联合，有或无组胺H1和H2 受体阻断剂和5-脂氧合酶抑制剂。（3）这些影响 将测定化合物对脑血容量的影响。3C）电子 显微镜也将被用来确定增加的机制， 磁导率3D）通过这些细胞向不同大小的分子开放BBB 将确定化合物。4)5-脂氧合酶转录本将 进一步以人类脑肿瘤为特征。5)研究将确定 在实验性肿瘤中， 颈动脉内输注白三烯和其他血管活性化合物。

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.