EFFECTS OF AN INTRATUMORAL INJECTION OF HUMAN RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA ON CEREBROVASCULAR PERMEABILITY AND LEUKOCYTIC INFILTRATION IN A RAT GLIOMA MODEL

The pro-inflammatory and blood-brain barrier (BBB) effects of intratum oral (IT) injection of human recombinant tumor necrosis factor-alpha ( rTNF-alpha) were studied in the Fischer rat RT-2 glioma model. Animals received a single stereotaxic injection of either 6x10(4) U rTNF-alph a or excipient (vehicle) into the center of an intracerebrally implant ed glioma. In order to demonstrate any effects rTNF-alpha might have o n the BBB, studies were conducted using endogenous IgG (150 kD) as a t racer. Forty-eight hours following injection of excipient, a margin of peritumoral IgG extravasation was observed while rats treated with 6x 10(4) U rTNF-alpha showed a dense and extensive IgG extravasation invo lving both hemispheres. Histological examination revealed that an IT r TNF-alpha injection induced leukocytic adherence, neutrophilic cuffing and infiltration throughout the lesion from 12 to 72 h after injectio n. These histological observations were supported by quantification of cerebral myeloperoxidase (MPO) levels which indicated a significant i ncrease in neutrophils over the excipient recipients at 4 and 12 h. Th ese MPO levels contrasted with our earlier studies in normal rats whic h revealed no significant difference in tissue MPO levels following in jection of excipient or rTNF-alpha. In addition, when MPO levels in tu mor models and normal rats receiving TNF were compared, a significantl y greater presence of neutrophils was seen in tumor models at 12 h pos t-TNF injection. We believe that the increased inflammatory response s een in a progressing glioma compared to normal brain may be the result of decreased resistance to leukocytic infiltration due to increased v ascular surface area, the lack of infiltration-resistant perivascular basement membrane, and/or increased extracellular space.