AdvisorRosen, Gerald M., Ph.D., J.D.
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AbstractPhagocytes, neutrophils and macrophages, are part of the non-specific host defense system in control bacterial infection by the phagocytosis and killing of these microbes through free radical-dependent and free radical-independent mechanisms. In contrast, endothelial cells, in addition to their role in maintenance of homeostasis, have classically been perceived to play a supportive role in host immune response by releasing chemoattractants that recruit phagocytes to the site of infection. Recent studies have, however, demonstrated that the endothelium is capable of responding to stimulation by cytokines as part of their activation responses in host immunity. This dissertation explores the role of endothelia as effector cells in host response. The findings from this dissertation demonstrated that endothelial cells cultured on three dimensional GelfoamRTM are activated by penicillin G to phagocytosis and kill S. aureus. Even though O2-· and NO· are known to exhibit microbicidal activity, it appears that these free radicals do not play an integral part in the observed killing of S. aureus. To further investigate the host defense role of NO·, primary cultures of endothelial cells were transduced with retroviral vector encoding NOS II gene. Upon transduction, these cells released NO· at a constant flux over a long period of time. This provided an excellent model to study the antimicrobial activity of NO· at cellular fluxes without the complications of controlling the rate of NO· from a NO·-releasing compound or those associated with cytokine treatment. When infected with either S. aureus or E. coli, NOS II transduced endothelial cells, producing NO·, phagocytosed both bacteria. However, only E. coli was sensitive to NO· dependent bacterial killing. Taken together, these studies reveal the antimicrobial roles played by endothelial cells upon activation. The mechanisms utilized by these cells include both free radical-dependent and free radical-independent pathways.
DescriptionUniversity of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 1999
Health Sciences, Pharmacology
Health Sciences, Immunology