1538 Localization of Matrix Degradation by Macrophages

Macrophages, which secrete proteolytic enzymes capable of hydrolyzing elastin, collagen, and glycoproteins, may play a prominent role in the turnover of connective tissue macromolecules at inflammatory sites. Their degradative capacity has been demonstrated on purified connective tissue substrates (1-6) and on complex extracellular matrices produced by cultured smooth muscle cells (SMC), x fibroblastic cells, and endothelial cells (7). Although macrophages in culture degrade these extracellular matrices to amino acids (8, 9), the precise localization of the matrix solubilization is not known. Endocytosis of insoluble matrix components would be virtually impossible without limited extracellular proteolysis. Understanding of the regulation of this degradation is complicated by the observation that neutral proteinases are secreted by cells along with proteolytic inhibitors (7, 10-12). In addition to extracellular digestion by neutral proteinases and intracellular digestion by lysosomal hydrolases, there is a third location for matrix solubilization at the cell surface and in the pericellular space. This zone differs from other extracellular sites because (a) local saturation of proteinase inhibitors may take place there, (b) cellular metabolism, including lactate production, could lower local pH so that lysosomal hydrolases could participate in matrix degradation, and (c) cell surface-bound enzymes could participate directly in degradation. All three of these are possibilities for the macrophage. At least some fibrinolysis is catalyzed by plasminogen activator in the presence of overwhelming plasma protein inhibitors (13), and it is known that osteoclasts create extracellular pockets where lysosomal enzymes are secreted (14). Lysosomal enzymes are also secreted during phagocytosis (15). Cell surface proteinases and serine esterases have been identified on mononuclear phagocytes (16-19) and have been shown to participate in amyloid degradation and cell movement (18, 19). The aim of the present study was to determine the localization of macrophage-