Inhibition of radiation-induced up-regulation of leukocyte adhesion to endothelial cells with the platelet-activating factor inhibitor, BN52021.
OBJECTIVE
The inflammatory process is likely involved in normal tissue damage after radiation exposure, yet few studies have directly evaluated the factors that might be involved in the regulation of inflammation after irradiation in vivo. We tested the hypothesis that platelet-activating factor, a neutrophil agonist synthesized by endothelial cells, is involved in the upregulation of radiation-induced leukocyte-endothelial cell interactions by using an inhibitor of its receptor, BN52021.


METHODS
Fischer-344 rats with dorsal skin-fold window chambers were randomized to three experimental groups: control (sham irradiation); 6 Gy radiation; and 6 Gy + BN52021. BN52021 (0.5 mg/kg) was administered 5 min prior to 6 Gy radiation. Leukocytes were stained in vivo with i.v. acridine orange for visualization with fluorescent microscopy. Venous vessel diameters were measured and number of rolling leukocytes were counted per 30-s period. The number of adhering leukocytes per unit surface area was also determined. Differences among the three experimental groups for rolling and adhering leukocytes were analyzed using a mixed-effects linear model with vessel shear rate used as a covariate. Results are reported as means +/- standard errors.


RESULTS
Irradiation caused upregulation of leukocyte rolling, as compared with sham-treated controls (p = 0.04): the BN compound in addition to radiation did not downregulate this effect. Irradiation also upregulated leukocyte adhesion (p < 0.001), but the addition of BN52021 prior to irradiation blocked this effect. The drug did not affect heart rate or blood pressure.


CONCLUSIONS
These results support the hypothesis that radiation-induced upregulation of leukocyte adhesion is mediated by platelet-activating factor. These results are consistent with prior reports that platelet-activating factor is not involved in leukocyte rolling, which involves separate families of adhesion molecules from those that regulate adhesion. BN52021, a ginkolide, or other related drugs might provide a useful pharmacological means to prevent or ameliorate inflammatory pathways that are invoked after radiation exposure.
Kimura
H
H
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Wu
N Z
NZ
Dodge
R
R
Spencer
D P
DP
Klitzman
B M
BM
McIntyre
T M
TM
Dewhirst
M W
MW
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects* / Q000528:radiation effects; D002450:Cell Communication / Q000187:drug effects* / Q000528:radiation effects; D004224:Diterpenes; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000528:radiation effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D046934:Ginkgolides; D007783:Lactones / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000528:radiation effects*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation / Q000187:drug effects* / Q000528:radiation effects*
D004224:Diterpenes; D005343:Fibrinolytic Agents; D046934:Ginkgolides; D007783:Lactones; C045856:ginkgolide B