Studies are proposed to examine if platelet/neutrophil activation and the consequent glomerular binding of released cationic proteins cause altered glomerular permeability to immune complexes during the early pathogenesis of glomerulonephritis. THe studies will utilize the following experimental models: In the first, inflammatory cells will be activated by intrarenal arterial infusions of synthetic platelet-activating factor (PAF) to cause release of endogenous PAF from basophils. The effects of ensuing cationic protein release will be tested by measuring glomerular permeability to macromolecules and pre-formed soluble immune complexes. In the second, BSA will be infused into the renal arteries in BSA immunized rabbits. The immune complexes formed in vivo will act as triggers for cell activation and cationic protein release. In the third, the biology of inflammatory cell activation, cationic protein binding and immune complex deposition in glomeruli will be studied in the rabbit model of acute serum sickness. Pharmacologic interventions will be employed to blunt inflammatory cell activation by prostacyclin-theophylline, ticlopidine, or anti-platelet/anti-neutrophil sera or neutralize cationic preoteins (by heparins) and thus attempt to decrease immune complex deposition. In addition, a common feature of glomerulonephritis is the development of hypercellularity as the result of infiltration of blood-borne inflammatory cells and/or the proliferation of resident glomerular cells. Studies are proposed to examine the potential roles of biologically active platelet cationic proteins in the recruitment of inflammatory cells to glomerular structures and/or the proliferation of resident glomerular cells in immune and non-immune models of progressive glomerular disease. Glomerular hypercellularity will be induced by: (1) Formation of large intraglomerular immune complexes and by infusion of BSA in preimmunized rabbit as outlined above; (2) Surgical ablation of 1 and 5/6 of the total renal mass leading to hyperfiltration of the remnant kidney; (3) Desoxycorticosterose-salt induced hypertension; and (4) Intravenous administration of Habu snake venom. Therapeutic interventions with the anti-platelet drug ticlopidine, anti-platelet serum and heparin will be employed to blunt platelet activation and attempt to ameliorate glomerular hypercellularity.
