Hypoxic injury to human alveolar macrophages accelerates release of previously bound neutrophil elastase. Implications for lung connective tissue injury including pulmonary emphysema.
Human neutrophil elastase and other neutrophil granule constituents are internalized by human alveolar macrophages in vitro via receptor-mediated endocytosis, and immunoreactive neutrophil elastase is detectable within alveolar macrophages freshly harvested from human smokers. To gain insight into the potential role of neutrophil elastase bound by alveolar macrophages in the pathogenesis of connective tissue proteolysis, we have chosen hypoxia as a model of macrophage injury and have studied its effect upon the fate of bound neutrophil elastase. We found (1) that in a 3-h incubation after brief exposure to neutrophil elastase, control alveolar macrophages partially degraded bound enzyme, but they also released intact, enzymatically active, elastase in small amounts; (2) that release of TCA-insoluble radiolabeled elastase and elastase activity was enhanced fivefold and twofold over control, respectively, by alveolar macrophage injury during a 3-h incubation in humidified nitrogen; (3) that enzymatic activity of bound neutrophil elastase was largely masked by human neutrophil elastase-inhibitory activity of macrophage cell extracts. The data suggest (1) that the fate of neutrophil elastase bound to alveolar macrophages may be modulated by the local tissue environment; (2) that noxious agents may cause proteolytic tissue injury in the vicinity of alveolar macrophages by enhancing release of bound neutrophil elastase; (3) that alveolar macrophages may participate in the pathogenesis of centrilobular pulmonary emphysema by serving as a vector for neutrophil elastase, even if elastase activity is not detectable in alveolar macrophage lysates.
D003238:Connective Tissue / Q000201:enzymology; D003594:Cytoplasmic Granules / Q000201:enzymology; D004705:Endocytosis; D005110:Extracellular Space / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000201:enzymology*; D008858:Microscopy, Phase-Contrast; D009504:Neutrophils / Q000201:enzymology*; D010100:Oxygen; D010196:Pancreatic Elastase / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology*; D011656:Pulmonary Emphysema / Q000201:enzymology*
D010196:Pancreatic Elastase; D010100:Oxygen