LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

了解调节血脑屏障（BBB）的机制， 血肿瘤屏障（BTB）的渗透性，以及选择性地 生物化学调节BTB通透性具有重要的治疗作用 影响 白三烯增加全身性血管通透性 但不是正常的脑毛细血管。 这可能与A 脑毛细血管中独特的“酶屏障”， 血管活性化合物，如白三烯。 显著相关 在缺血性脑损伤中， 脑毛细血管和γ谷氨酰转肽酶的丢失 （gammaGTP）在脑毛细血管中。 同样的相关性也存在于 脑瘤 白三烯（LT）C4将选择性地打开BTB， 实验肿瘤的两倍，而不增加渗透性， 周围大脑正常。 正常的脑毛细血管，不像全身 毛细血管和脑肿瘤毛细血管，有高浓度的 γ GTP γ GTP将LTC 4转化为LTD 4。 虽然抑制 γ-GTP与阿西维星将增强血脑屏障开放的白三烯， 缺血性脑组织，单独用阿西霉素抑制可能不会导致 正常组织中白三烯BBB开放。这些发现表明 其它酶也可组成“酶促”血脑屏障。 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 肿瘤中的BBB渗透性。 根据这些发现，我们有 表明，白三烯可以允许增加交付的 抗肿瘤药物对肿瘤组织的作用 相反，抑制 5-脂氧合酶可减轻脑肿瘤水肿。 进一步调查 白三烯和血脑屏障：1A）在患有脑肿瘤的大鼠中， 脑血流量和血容量后，颈动脉（IC）白三烯 将定量输注;和1B）将使用电子显微镜 以确定LT增加BBB的机制是否 渗透性，是通过打开紧密连接或增加胞饮细胞 运输 1C）BTB的不同大小的白三烯开口 分子将被确定。2A）鉴定另一种可能的酶， “酶屏障”，二肽酶（ 将LTD 4转化为LTE 4）用于确定二肽酶是否 存在于脑毛细血管中，如果存在，它是否在脑中丢失 肿瘤或局部缺血。 为了进一步理解“酶屏障”，2B） 其他血管活性化合物，缓激肽和组胺，也可以允许 选择性BBB开放将单独输注IC和与 白三烯，有和没有组胺H1和H2受体阻滞剂， 5-脂氧合酶抑制剂。 2C）对γ GTP抑制的剂量响应 由acivicin到LTC 4的开放将被确定。3)5-脂氧合酶 转录物将在人脑肿瘤中进一步表征。四、 研究将确定是否药物渗透性增加， 实验肿瘤后，颈动脉灌注白三烯。

Understanding the mechanisms that regulate blood-brain barrier (BBB) and blood-tumor barrier (BTB) permeability, and the ability to selectively modulate BTB permeability biochemically has important therapeutic implications. Leukotrienes increase vascular permeability in systemic capillaries but not normal brain capillaries. This may relate to a unique "enzymatic barrier" in brain capillaries that inactivate vasoactive compounds, like leukotrienes. A significant correlation exists between increased BBB permeability by leukotrienes in ischemic brain capillaries, and the loss of gamma glutamyl transpeptidase (gammaGTP) in brain capillaries. The same correlation also exists in brain tumors. Leukotriene (LT) C4 will selectively open the BTB in experimental tumors two-fold without increasing permeability in the normal surrounding brain. Normal brain capillaries, unlike systemic capillaries, and brain tumor capillaries, have high concentrations of gammaGTP. Gamma GTP converts LTC4 to LTD4. Although inhibition of gammaGTP with acivicin will enhance BBB opening by leukotrienes in ischemic brain tissue, inhibition with acivicin alone may not result in leukotriene BBB opening in normal tissue. These findings suggest that other enzymes may also compose the "enzymatic" BBB. 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 BBB permeability in tumors. 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 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. 1C) Leukotriene opening of the BTB to different size molecules will be determined. 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 brain capillaries, and if so, whether it is lost in brain tumors or ischemia. To further understand the "enzymatic barrier," 2B) 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. 2C) The dose response to gammaGTP inhibition by acivicin to LTC4 opening will be determined. 3) 5-lipoxygenase transcripts will be further characterized in human brain tumors. 4) Studies will determine whether permeability to drugs is increased in experimental tumors after intracarotid infusion of leukotrienes.