LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

了解调节血脑屏障（BBB）的机制

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.