Inflammation, Metalloproteinases, Chronic Venous Disease and Sulodexide

Abstract Inflammation and extracellular Matrix Metallo Proteinases (MMPs) have been recently considered as an important step in the pathogenesis of Chronic Venous Disease (CVD). To understand how inflammation and MMP may affect venous tissue, a review on these items and on the pathogenesis of CVD was performed. Prolonged or repeated venous hypertension due to well-known predisposing factors causes abnormal shear stress leading to shredding of endothelial glycocalyx and activation of endothelial cells. The latter expose adhesion molecules and release pro-inflammatory cytokines. Diapedesis follows, leading to leukocytes infiltration of Extra Cellular Matrix (ECM) in the sub endothelial space of vein walls and valves. Activated leukocytes, mainly monocytes-macrophages, release chemotactic cytokines that amplify the inflammatory response, they also produce Nitric Oxide molecules (NO) and proteases, including MMPs. High concentration of MMPs, especially MMP-9, is found in venous wall with CVD and in venous ulcers. The role of MMP-9 in CVD is also supported by experimental data. MMP-9 can degrade components of ECM as collagen, elastin, fibronectin and laminin. MMP-9 and other proteolytic enzymes may disrupt ECM structure, damaging and debilitating venous wall that lead to varicose veins and venous ulcers. Sulodexide, a glycosaminoglycan, counteracts several of these inflammatory changes. In subjects with CVD administration of sulodexide improves venous hemodynamic changes and CVD symptoms and accelerates venous leg ulcers healing.