Acute ischemia followed by reperfusion is associated with edema formation in skeletal muscle of the extremities. If severe, the edema can lead to compressive decreases in tissue perfusion and loss of the limb. Investigations in this laboratory are directed towards studying the neutrophil mediated inflammatory response which appears to be the initial cause of edema formation. Recent studies on anesthetized rabbits following tourniquet ischemia indicate that a decrease in the amount and the size of hyaluronan may cause chronic edema formation following the acute changes in microvascular protein permeability. Hyaluronan is the major polysaccharide in the extracellular matrix of most tissues and provides hydrated areas through which cells, proteins and other molecules can move. Oxygen radicals released during an inflammatory response can easily cause hyaluronan depolymerization and disruption of the extracellular matrix. The time dependent changes in hyaluronan depolymerization and synthesis are studied in vivo following ischemia-reperfusion to test the hypothesis that ischemia disrupts synthesis while activated neutrophils cause depolymerization, leading to chronic edema. Oxygen radical scavengers and iron chelators are used to inhibit hyaluronan depolymerization. Additional studies are focused on identifying the cytokines that control hyaluronan synthesis and cellular uptake by cultured endothelial cells or fibroblasts.