Experimental models to investigate inflammatory processes in chronic venous insufficiency

Chronic venous insufficiency (CVI) is characterized by leukocyte adhesion a nd infiltration: venous hypertension and dilatation, and valvular dysfuncti on. The fact that activated white cells can direct a powerful cytotoxic ars enal at parenchymal cells following their extravasation into the tissues le d to the original proposal that leukocytes ma!; play a causative role in th e pathogenesis of venous disease. A large body of subsequent work; indicate s that white blood cells are indeed activated in CVI. I-Ion ever identifica tion of the factors responsible for initiating leukosequestration and activ ation in such disorders and determinization of whether these activated cell s then contribute to the progression of venous disease have been hampered b y the lack of appropriate animal models that accurately mimic the human con dition. Tantalizing evidence suggesting that cyclical periods of ischemia a nd reperfusion (I/R) may occur in diseased regions of the skin is beginning to accumulate. As is the case with CVI, leukocyte infiltration is a promin ent feature in I/R and activated neutrophils play a causative role in the r eperfusion component of tissue injury via the targeted release of reactive oxygen metabolites and hydrolytic enzymes. In light of these considerations , many investigators hare suggested that examining;he mechanisms of I/R inj ury in skin and skeletal muscle, where ischemia is produced by arterial occ lusion, ma?; provide a relevant model for studying the pathogenesis of CVI. Others have suggested chat venous occlusion may represent a more appropria te model, as this approach also produces the venous hypertension that is ch aracteristic of the disease. The purpose of this review is to summarize the evidence pointing to the involvement of I/R and venous hypertension as cau sative factors ill CVI-induced leukocyte recruitment. In addition, we will describe the evidence in favor of the view that white blood cells contribut e to the pathogenesis of CVI. Finally, we will describe several different e xperiment models that have been used to examine the role of I/R-induced mic rovascular dysfunction as it may pertain to the development of CVI together with a discussion of the relative advantages and limitations of the variou s models.