Sickle cell anemia patients suffer end organ damage due to vaso-occlusion. Over the past two decades investigations of red blood cell/vessel wall interactions have led to a revised paradigm for the understanding of vaso-occlusive phenomena in sickle cell disease. Clinical conditions associated with inflammation such as infections, surgery and others exacerbate crises in sickle cell anemia patients. Preliminary data demonstrate that patients with sickle cell disease have markers of inflammation including elevated C-reactive protein levels and activated monocytes. In vitro these monocytes activate human endothelial cell NF-kB and adhesion molecule expression. Transgenic mouse models of human sickle cell disease also have markers of inflammation, including elevated white blood cell counts and activated monocytes. This proposal posits that an inflammatory phenotype augments tissue injury through worsened vasoocclusion. Thus, inflammation augments vaso-occlusion while anti-inflammatory agents may minimize vaso-occlusion. The project will examine these hypotheses in transgenic mouse models of human sickle cell disease: (1) Anti-inflammatory agents decrease vascular inflammation and improve blood flow. (2) Pro-inflammatory agents such as murine cytomegalovirus, lipopolysaccharide and hypoxia/reoxygenation, increase vascular inflammation and worsen vaso-occlusion. (3) TNF-alpha, IL-1 beta and CD18 transgenic knockout mice that express human betaS hemoglobin have decreased vascular inflammation and improved blood flow parameters. These studies will provide information for understanding the role of the inflammatory response and its relationship to vaso-occlusion in sickle cell disease and serve as an important foundation for developing new and novel therapies to prevent organ dysfunction.
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