title: Effect of tumor necrosis factor-alpha on the permeability of bovine brain microvessel endothelial cell monolayers.
abstract: The administration of chemotherapy to patients with tumors of the central nervous system is often blocked by the blood-brain barrier. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that promotes vascular permeability in addition to its pro-inflammatory effects. However, no direct evidence exists as to whether TNF-alpha may increase permeability of the BBB. We evaluated the effect of TNF-alpha on the transport of cisplatin (CDDP) or high molecular weight dextran labeled with fluorescein isothiocyanate (FITC-dextran) across bovine brain microvessel endothelial cell (BMEC) monolayers that was conducted on side-by-side diffusion chambers in vitro. The permeability coefficient for the transport of CDDP across the untreated monolayer was 3.80 x 10(-5) cm sec-1 at 30 minutes. After treating the BMEC monolayer with TNF-alpha (50 U ml-1 and 500 U ml-1) for 36 hours, the PC of CDDP increased significantly to 8.94 x 10(-5), and 14.43 x 10(-5) cm sec-1 respectively (p < 0.01). TNF-alpha had no effect on the transport of FITC-dextran across the BMEC monolayers. Electron microscopy showed that the tight junctions between the BMECs persisted even after treatment with TNF-alpha, whereas they had been partially disrupted following exposure to mannitol, 1600 mOsm kg-1. TNF-alpha selectively promoted the in vitro permeability of the blood-brain barrier to CDDP without disrupting tight junctions. This system could be used as a model for experimental studies of chemotherapy. Findings suggested that the combined administration of TNF-alpha and CDDP may be clinically useful.
authors.affiliation: Department of Neurosurgery, Nagasaki University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Anda
authors.forename: H
authors.initials: H
authors.lastname: Yamashita
authors.forename: H
authors.initials: H
authors.lastname: Khalid
authors.forename: K
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: H
authors.initials: H
authors.lastname: Fujita
authors.forename: Y
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: S
authors.initials: S
authors.lastname: Shibata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000098:blood supply*; D002417:Cattle; D002478:Cells, Cultured; D002945:Cisplatin / Q000493:pharmacokinetics*; D003911:Dextrans / Q000493:pharmacokinetics; D015194:Diffusion Chambers, Culture; D004234:Diuretics, Osmotic / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008353:Mannitol / Q000494:pharmacology; D008854:Microscopy, Electron; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D004234:Diuretics, Osmotic; D014409:Tumor Necrosis Factor-alpha; C015219:fluorescein isothiocyanate dextran; D008353:Mannitol; D016650:Fluorescein-5-isothiocyanate; D002945:Cisplatin