LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

了解调节血脑屏障(BBB)和 血-肿瘤屏障(BTB)的通透性和选择性 生化调节血细菌通透性具有重要的治疗意义 这意味着什么。白三烯增加全身血管通透性 毛细血管，但不是正常的大脑毛细血管。这可能与 脑毛细血管中独特的失活“酶屏障” 血管活性化合物，如白三烯。显著的相关性 白三烯致脑缺血大鼠血脑屏障通透性增加 脑毛细血管和γ-谷氨酰转肽酶的丢失 (GammaGTP)。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 在不增加肿瘤渗透性的情况下将实验肿瘤扩大两倍 周围大脑正常。正常的大脑毛细血管，不像全身性的 毛细血管和脑瘤毛细血管中有高浓度的 GammaGTP。Gamma GTP将LTC4转换为LTD4。虽然抑制了 γ-GTP与阿昔维星联合应用可增强白三烯对大鼠血脑屏障的开放作用 脑缺血组织，单用阿昔维菌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， 其他酶也可能组成“酶”血脑屏障。 LTC4在人脑肿瘤中的表达与其含量有关 肿瘤周围的水肿症。人脑肿瘤表达花生四烯酸 5-脂氧合酶基因及对5-脂氧合酶抑制作用将减弱 肿瘤的血脑屏障通透性。根据这些发现，我们有 提示白三烯可以增加药物的释放 抗肿瘤药物对肿瘤组织的作用。相反，抑制 5-脂氧合酶可减轻脑瘤水肿。进一步调查 白三烯和BBB：1A)在脑瘤大鼠中的变化 颈内动脉注射白三烯后的脑血流量和血容量 输液将被量化；并将使用电子显微镜 为了确定LT增加血脑屏障的机制 通透性，是通过打开紧密连接或增加胞饮 运输。1c)不同大小的BTB的白三烯开口 分子将被确定。2a)确定另一种可能的酶 “酶屏障”，即二肽酶的抗血清(这种酶 将LTD4转换为LTE4)用于确定二肽酶是否 存在于大脑毛细血管中，如果是的话，它是否在大脑中消失 肿瘤或脑缺血。为了进一步理解“酶的障碍”，2B) 其他血管活性化合物，缓激肽和组胺，也可能允许 选择性BBB开口将单独注入IC，并与 白三烯，有或没有组胺H1和H2受体阻滞剂和 5-脂氧合酶抑制剂。2C)对GTP抑制的剂量反应 通过Acivicin对LTC4的开放将被确定。3)5-脂氧合酶 转录本将在人脑肿瘤中进一步表征。4) 研究将确定药物的渗透性是否在 颈动脉内注射白三烯后的实验性肿瘤。

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.