Radiation-induced astrogliosis and blood-brain barrier damage can be abrogated using anti-TNF treatment.
OBJECTIVE
In this article, we investigate the role of tumor necrosis factor-alpha (TNF) in the initiation of acute damage to the blood-brain barrier (BBB) and brain tissue following radiotherapy (RT) for CNS tumors.


METHODS
Intravital microscopy and a closed cranial window technique were used to measure quantitatively BBB permeability to FITC-dextran 4.4-kDa molecules, leukocyte adhesion (Rhodamine-6G) and vessel diameters before and after 20-Gy cranial radiation with and without treatment with anti-TNF. Immunohistochemistry was used to quantify astrogliosis post-RT and immunofluorescence was used to visualize protein expression of TNF and ICAM-1 post-RT. Recombinant TNF (rTNF) was used to elucidate the role of TNF in leukocyte adhesion and vessel diameter.


RESULTS
Mice treated with anti-TNF showed significantly lower permeability and leukocyte adhesion at 24 and 48 h post-RT vs. RT-only animals. We observed a significant decrease in arteriole diameters at 48 h post-RT that was inhibited in TNF-treated animals. We also saw a significant increase in activated astrocytes following RT that was significantly lower in the anti-TNF-treated group. In addition, immunofluorescence showed protein expression of TNF and ICAM-1 in the cerebral cortex that was inhibited with anti-TNF treatment. Finally, administration of rTNF induced a decrease in arteriole diameter and a significant increase in leukocyte adhesion in venules and arterioles.


CONCLUSIONS
TNF plays a significant role in acute changes in BBB permeability, leukocyte adhesion, arteriole diameter, and astrocyte activation following cranial radiation. Treatment with anti-TNF protects the brain's microvascular network from the acute damage following RT.
Wilson
Christy M
CM
School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN, USA.
Gaber
M Waleed
MW
Sabek
Omaima M
OM
Zawaski
Janice A
JA
Merchant
Thomas E
TE
D000818:Animals; D000918:Antibody Specificity; D001160:Arterioles / Q000033:anatomy & histology / Q000187:drug effects / Q000528:radiation effects; D001253:Astrocytes / Q000187:drug effects / Q000528:radiation effects*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D001921:Brain / Q000098:blood supply / Q000528:radiation effects; D002448:Cell Adhesion / Q000187:drug effects / Q000528:radiation effects; D016543:Central Nervous System Neoplasms / Q000532:radiotherapy; D016371:Cranial Irradiation; D003911:Dextrans / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005455:Fluorescent Antibody Technique; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000528:radiation effects; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability / Q000187:drug effects / Q000528:radiation effects; D011829:Radiation Dosage; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D014699:Venules / Q000033:anatomy & histology / Q000187:drug effects / Q000528:radiation effects
D003911:Dextrans; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C015219:fluorescein isothiocyanate dextran; D018799:Intercellular Adhesion Molecule-1; D016650:Fluorescein-5-isothiocyanate