Aernoud Fiolet

96 Chapter 4 dampen the activity of the full palette of cellular players that mediate inflammatory injury in atherosclerotic plaque including neutrophils, macrophages, mast cells and T-cells. In addition, it affects endothelial and platelet function, alter the function of E-selectin on endothelial cells and decrease the adherence of leukocytes to inflamed endothelium. 13 It also can dampen the growth of vascular smooth muscle cells and fibrocytes that become activated in the healing response to vascular injury. 14-19 Importantly colchicine has proven safe and effective when used continuously over decades for the secondary prevention of acute inflammatory flares in patients with Familial Mediterranean Fever (FMF) and gout. 20-22 Figure 1. Effects of colchicine on inflammatory injury and healing in atherosclerotic plaque. The formation of cholesterol crystals (CC) in atherosclerotic plaques may lead to injury. Microscopic CCs may enlarge to form macroscopic CCs which can cause sudden unheralded disruption of the endothelium, or they may activate complement to trigger an inflammatory response by promoting entry of circulating leucocytes into the vascular bed by either directly activating endothelium to produce selectins (S) or by stimulating pro-inflammatory macrophage (M1) to release interleukin (IL)- 1 β which also acts to enhance recruitment of inflammatory cells into the vascular bed. If the CCs are not rapidly cleared the inflammatory response can persist, increasing the risk of inflammatory injury that may disrupt the endothelium and lead to atherothrombosis. As CCs are cleared, anti-inflammatory macrophages (M2) begin to dominate the milieu and release of anti-inflammatory cytokines including IL-10 and transforming growth factor (TGF)- β that suppress pro-inflammatory signals and promote the ingrowth of smooth muscle cells (SMC), fibrocytes (F) and cells with osteogenic potential (O) leading to the formation of fibro-calcific plaques. Colchicine inhibits the pro-inflammatory response to CCs by; (1) reducing macrophage expression of IL-1 β and the release of various cytokines including tumor necrosis factor (TNF)– α (2) reducing endothelial expression of selectins and (3) inhibiting the actions of circulating leucocytes including suppressing their ability to release lytic enzymes including Matrix Metalloproteinase and super-oxide. In addition, colchicine also (4) impairs platelet-leucocyte interactions that promote atherothrombosis and it can promote resolution and healing by (5) inhibiting over expression of IL-10 and TGF- β and (6) by limiting the growth of smooth muscle cells, fibroblasts and osteophytes that if unchecked leads tovascular thickening, deformity and calcification. (Reproduced with permission). 42