EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA ON THE PERMEABILITY OF BOVINE BRAIN MICROVESSEL ENDOTHELIAL-CELL MONOLAYERS

The administration of chemotherapy to patients with tumors of the cent ral 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 permeabil ity of the BBB. We evaluated the effect of TNF-alpha on the transport of cisplatin (CDDP) or high molecular weight dextran labeled with fluo rescein 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 tran sport 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 (5 0 U ml(-1) and 500 U ml(-1)) for 36 hours, the PC of CDDP increased si gnificantly to 8.94 x 10(-5), and 14.43 x 10(-5) cm sec(-1) respective ly (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-al pha, whereas they had been partially disrupted following exposure to m annitol, 1600 mOsm kg(-1). TNF-alpha selectively promoted the in vitro permeability of the blood-brain barrier to CDDP without disrupting ti ght junctions. This system could be used as a model for experimental s tudies of chemotherapy. Findings suggested that the combined administr ation of TNF-alpha and CDDP may be clinically useful.