Atherosclerosis and Inflammation

Abstract

ConclusionThere is conclusive evidence that atherosclerosis is a complex inflammatory process that begins early in life. Inflammatory reaction has been demonstrated in various stages of the atheromatous lesions in human and animal models. Furthermore, systemic markers of inflammation can predict future cardiovascular events in healthy populations. The process of initiation of atherosclerosis is not unlike that of the clotting cascade and similar to the inflammatory cascade in chronic infection. The differences may be only in the degree and extent of stimulation of the various reactions, and to specific types of cytokines stimulated which may dictate the type of cellular response. Whatever the nature of the initial insult that leads to endothelial injury, there follows a cascade of events-increased expression of adhesion molecules that stimulate adhesion, aggregation, and migration of leukocytes; upregulation of proinflammatory cytokines that causes further accumulation of leukocytes, foam cells, and lipids and at the same time stimulate hepatocytes to increase acute phase reactants; continued stimulation of cytokines and various tissue growth factors that influence migration and proliferation of smooth-muscle cells, fibroblasts, and leukocytes. It has been postulated that IL-6, an end product of TNF-α and IL-1; upregulation, is the central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity98,99. IL-6 is a powerful inducer of the hepatic acute phase response, such as fibrinogen, CRP, and SAA, which are strong risk factors for CHD, and is associated with increased blood viscosity, platelet number, and activity. Furthermore, raised SAA lowers HDL-cholesterol levels (which are protective against atherosclerosis). IL-6 also decreased lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and the fibrous caps and shoulder regions of atheroma, macrophage foam cells and smooth-muscle cells express IL-6, along with IL-1β and TNF-α indicating that the cytokines play a role in atherogenesis. Furthermore, circulating IL-6 stimulates the hypothalmic-pituitary-adrenal axis, activation of which is associated with central obesity, hypertension, and insulin resistance99.