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Figure 5 An inflammatory pathway links risk factors to altered cellular behavior and elevated inflammatory markers in peripheral blood. The primary proinflammatory risk factors depicted on the top of this diagram activate the various cell types prominent in the atherosclerotic plaque, including the macrophage, endothelial cells (EC), smooth muscle cells (SMC), and in complicated lesions, the activated platelet. These various cell types in turn can secrete inflammatory mediators and reactive oxygen species (ROS). The ECs will express leukocyte adhesion molecules that can be shed and recovered in a soluble form in the peripheral blood. The primary proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha, can stimulate large amounts of IL-6 production by intrinsic vascular wall cells. This heightened IL-6 production represents an amplification loop, because 1 molecule of a primary proinflammatory cytokine can beget the expression of many more molecules of IL-6. The IL-6 can function as a messenger, traveling through the peripheral blood to the liver, where it alters the program of gene expression to elicit the acute-phase response. The acute-phase reactants include C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, and plasminogen activator inhibitor-1. Among these acute-phase reactants, CRP has proved to be a robust prospective indicator of cardiovascular events in a wide spectrum of individuals. Activated platelets release a number of inflammatory mediators, including CD40 ligand, which is also shed in a soluble form. The CD40 ligand can activate tissue factor gene expression, providing a positive feedback reinforcement of thrombosis in an inflammatory milieu. AGE = advanced glycation end products; Ang II = angiotensin II; MMPs = matrix metalloproteinases; OxLDL = oxidized low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1; RANTES = Regulated on Activation, Normal T Cell Expressed and Secreted (also known as chemokine ligand 5, CCL5).
