All ETDs from UAB

Advisory Committee Chair

Dennis F Kucik

Advisory Committee Members

Susan Bellis

Daniel Bullard

Joanne Murphy-Ullrich

Casey Weaver

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Exposure to radiation from a variety of sources is associated with increased risk of heart disease and stroke. Since radiation also induces inflammation, a possible mechanism is a change in the adhesiveness of vascular endothelial cells, triggering pro-atherogenic accumulation of leukocytes. To investigate this mechanism at the cellular level, the effect of xrays, iron (Fe56) ions, and protons on adhesiveness of cultured human aortic endothelial cells (HAECs) was determined. HAECs were grown as monolayers and exposed to 0 to 30 Gy X-rays, 0, 2, and 5 Gy Fe56 ions, and 0, 0.5, and 2 Gy protons followed by measurement of adhesiveness under physiological shear stress using a flow chamber adhesion assay. HAEC adhesiveness was then measured at 24 and 72 hour time points. Differences were found in peak dose and adhesivity between x-rays, iron ions, and protons. A peak effect was seen with 15 Gy x-rays at 24 hours, radiation had no effect 72 hours later. 2Gy and 5 Gy Fe56 ion irradiated cells were highly adhesive at both 24 and 72 hour time points. Finally protons showed a biphasic response, where 2 Gy is highly adhesive at 24 hours; 72 hours later 0.5 Gy is the peak dose. Despite the differences seen in adhesivity radiation had no significant effect on surface expression of the endothelial adhesion molecules ICAM-1 or VCAM-1. Antibody blockade of the leukocyte integrin receptors for ICAM- 1 and VCAM-1, however, abolished the radiation-induced adhesiveness. Since these leukocyte integrins can be activated by chemokines presented on the endothelial cell surface, the effect of pertussis toxin (PTX), an inhibitor of chemokine-mediated integrin activation, was tested. PTX specifically inhibited radiation-induced adhesiveness, with no significant effect on non-irradiated cells. Therefore, radiation induces increased adhesiveness of aortic endothelial cells through chemokine-dependent signaling from endothelial cells to leukocytes, even in the absence of increased expression of the adhesion molecules involved.

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