Effects of polyunsaturated fatty acids on mediators of inflammation associated with atherosclerosis

Abstract

The inflammatory pathogenesis of atherosclerosis has been defined, largely by the “response to injury” hypothesis. The morphological development of atherosclerosis has also been defined. Monocytes and lymphocytes accumulate in infancy at lesion-prone sites and are believed to mitiate the atherosclerotic process in response to endothelial injury. They transmigrate across dysregulated endothelium from the circulation to the subendothelial space. Monocytes differentiate to macrophages, and the foam cell derivative is a major contributor to the necrotic core or “gruel” of the lesion. The secretory products of resident inflammatory cells mediate lesion progression. Lymphocytes, monocytes, macrophages and dendritic cells potentiate the dysregulation of endothelial cells and induce the proliferation and transmigration of the normally quiescent smooth muscle cell. The immune cells are vital by their protective capacity and their accumulation at the arterial wall is not clinically significant. Their reaction to endothelial injury, however, changes the dynamic in their function from physiological to pathological. Modulation of the inflammatory phenotype of cells that initiate and promote atherosclerosis could, potentially, mute the aggressive and dysregulated processes of lesion development. Fatty acids are known to modulate immune responses. This thesis investigates the effects of a number of polyunsaturated fatty acids (PUFA) on inflammatory mediators of lymphocytes, monocytes and macrophages associated with atherosclerosis, in vivo, ex vivo and in vitro.