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 intratumoral (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 6 x 10(4) U rTNF-alpha or excipient (vehicle) into the center of an intracerebrally implanted glioma. In order to demonstrate any effects rTNF-alpha might have on the BBB, studies were conducted using endogenous IgG (150 kD) as a tracer. Forty-eight hours following injection of excipient, a margin of peritumoral IgG extravasation was observed while rats treated with 6 x 10(4) U rTNF-alpha showed a dense and extensive IgG extravasation involving both hemispheres. Histological examination revealed that an IT rTNF-alpha injection induced leukocytic adherence, neutrophilic cuffing and infiltration throughout the lesion from 12 to 72 h after injection. These histological observations were supported by quantification of cerebral myeloperoxidase (MPO) levels which indicated a significant increase in neutrophils over the excipient recipients at 4 and 12 h. These MPO levels contrasted with our earlier studies in normal rats which revealed no significant difference in tissue MPO levels following injection of excipient or rTNF-alpha. In addition, when MPO levels in tumor models and normal rats receiving TNF were compared, a significantly greater presence of neutrophils was seen in tumor models at 12 h post-TNF injection. We believe that the increased inflammatory response seen in a progressing glioma compared to normal brain may be the result of decreased resistance to leukocytic infiltration due to increased vascular surface area, the lack of infiltration-resistant perivascular basement membrane, and/or increased extracellular space.
Wright
J L
JL
Department of Anatomy, Virginia Commonwealth University, Medical College of Virginia, Richmond 23298, USA.
Merchant
R E
RE
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects*; D002543:Cerebral Hemorrhage / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000473:pathology; D005910:Glioma / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D015552:Injections, Intralesional; D007276:Injections, Intraventricular; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use*
D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase