All ETDs from UAB

Advisory Committee Chair

Dennis F Kucik

Advisory Committee Members

Daniel Bullard

Janusz Kabarowski

Joanne Murphy-Ullrich

Rakesh Patel

Christopher Willey

Document Type

Thesis

Date of Award

2014

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

Ionizing radiation (IR) is a potent inflammatory stimulus to the human body. In the vasculature, inflammation is a major contributing factor for atherosclerosis. In addition, radiation from several sources has been linked with increased risk for multiple cardiovascular complications. A key compnent of radiation associated inflammation is an increase in the adhesiveness of the endothelium which leads to a pathogenic accumulation of leukocytes in the vascular wall. This is one of the initial steps in vascular inflammation and leads to a number of adverse complications such as heart disease and stroke. The molecular mechanisms behind radiaton enhanced endothelial adhesion have not been completely delineated. Our previous studies with HAECs interogating the molecular mechanism responsible for enhanced endothelial adhesiveness have shown that chemokine signaling is required. Further investigation using luminex technology and in-vitro laminar flow adhesion assays showed that IL-8 was in fact the chemokine responsible. 15 Gy X-ray radiation greatly induced secretion of IL-8 in an acute fashion. In addition inhibiting IL-8 completely ablated the adhesion enhanced by radiation. In addition treating unirradiated endothelial cells with both recombinant human IL-8 and media harvested from irradiated endothelial cells was able to replicate the adhesion effect seen after directly irradiating endothelial cells. Our studies also show that heparan sulfate glycosaminoglycan chains, which are responsible for chemokine presentation, present on the endothelial cell surface are also critical for radiation enhanced endothelial adhesion. Due to the soluble nature of IL-8 it is likely that heparan sulfate binds IL-8 secreted in response to radiation and then presents IL-8 to the chemokine receptors on flowing monocytic cells.

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