Alveolar macrophages have the capacity to secrete and take up proteases. Due to the central role played by macrophages in lung defense and mounting evidence demonstrating the involvement of proteases in lung disease the regulation of these disparate capabilities needs to be studied. In particular, proteases bound to the plasma protease inhibitor alpha macroglobulin can be internalized via high affinity surface receptors and once internalized induce collagenase secretion by macrophages. Additionally, recent studies suggest that macrophages may be capable of secreting alpha macroglobulins. To study the regulation of protease secretion rabbit alveolar macrophages will be obtained from normal rabbits or rabbits given inflammatory stimuli. The macrophages will be maintained in vitro and both basal rate and phagocytosis induced protease secretion studied. Specifically, we will determine if secreted proteases (collagenase, elastase, neutral proteases, plasminogen activator) are coordinately regulated or are separately induced. Analogous studies will also be carried out using rabbit peritoneal macrophages and peripheral monocyte phagocyte family. We also propose to determine the physiological parameters behind the induction of macrophage protease secretion induced by alpha macroglobulin protease complexes. In particular, whether other protease inhibitors (such as alpha l antitrypsin) or protease inhibitor complexes can modify the induction of macrophage protease secretion. It has been suggested that human monocytes may secrete alpha macroglobulin. Using monospecific antibodies to immunoprecipitate rabbit alpha 1 macroglobulin and alpha 2 macroglobulin we propose to determine if rabbit alveolar macrophages as well as blood monocytes can synthesize and secrete alpha macroglobulins and if so what factors regulate secretion of this protease inhibitor.
NIH ExPorter
NIH ExPorter