Elastin degradation by mononuclear phagocytes

Abstract

During their development, mononuclear phagocytes express a changing profile of proteinases that may participate in the degradation of elastin and other extracellular matrix components. Neutrophil elastase is produced and stored in azurophil-like granules in immature mononuclear phagocytes. Monocytes contain small amounts of neutrophil elastase but do not synthesize the enzyme. Macrophages neither synthesize nor contain neutrophil elastase, but they can internalize and secrete scavenged neutrophil elastase. Human alveolar macrophages synthesize cysteine proteinases including cathepsin L, a lysosomal enzyme with elastolytic activity at an acidic pH. Macrophages from several animal species synthesize an approximately 22-kD metalloelastase that, in the mouse, is secreted as a zymogen of about 36 kD. In addition to its direct elastolytic properties, this metalloelastase may also promote elastolysis by cleaving alpha 1-antiproteinase and thus protecting neutrophil elastase from inhibition. A human counterpart of this enzyme has not yet been purified; however, the elastolytic activity of human macrophages appears to depend predominantly on the activity of one or more metalloproteinases. Because elastin is intertwined with other matrix components in natural matrices, degradation of elastin in vivo probably involves cooperation of multiple proteinases to uncover macromolecules that mask the elastic fibers. Degradation of matrix may be localized to pericellular sites, where proteinases are protected from inhibitors and where potentially surface-bound enzymes may be concentrated. Complete breakdown of matrix may be completed within the cells after partially cleaved molecules are internalized. Growth and remodeling of the extracellular matrix must involve highly coordinated interactions between cells, cytokines, proteinases, proteinase activators and inhibitors, as well as the matrix itself. The intrapulmonary process resulting in emphysema probably involves equally complex interactions. Mononuclear phagocytes accumulate in large numbers in the lung in response to cigarette smoking, and they may play a role in the pathogenesis of the alveolar septal injury that characterizes pulmonary emphysema.