The inflammatory process is essential for host defense against infection and for survival. Two of the initial events of inflammation, increased vascular permeability and infiltration of phagocytic cells, are mediated by C3a and C5a, the samll cleavage fragments of the third (C3) and fifth (C5) components of complement (C). The experiments presented in this application will investigate the regulation of synthesis of the C3 and C5, and other acute phase proteins (APP), during inflammation. The first series of experiments will determine the regulation of synthesis of C3 and C5 in vitro by human macrophages (peripheral blood monocyte-derived macrophages). The role of agents that could be at active sites of inflammation in stimulating these cells to produce increased amounts of C3 and C5 will be determined. The stimuli to be used will include phagocytic particles, lipopolysaccharide and phospholipase A2. We will then determine if the C3 and C5 produced by the human macrophages are precursors for the phlogistic fragments, C3a and C5a, the activity of which will be measured using standard biologic assays. The second set of experiments will investigate the role of surfaces comprised of proteins present in inflammatory sites in supporting production of C by human macrophages. The proteins used will be fibrinogen, collagen, gelatin (denatured collagen) and fibronectin. Finally, in vivo synthesis rates of C3 and C5 (as well as ceruloplasmin, another APP) by liver will be measured at various times after induction of turpentine pleurisy in rabbits. We will then attempt to define the blood-borne, soluble mediator(s) responsible for the changes in synthetic rates of the APP using an in vitro system with rabbit liver cells. We will then determine if synthesis of each APP is controlled by a separate mediator, or if a single mediator controls synthesis of all the APP, and if a single APP can be controlled by more than one mediator.
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