Small specific peptides of the cyanobacterium Microcystis aeruginosa cause thrombocytopenia and pulmonary thrombosis without activation of the coagulation cascade. The pulmonary thrombosis apparently leads to pulmonary occlusion, right heart failure, hepatomegaly and death in mammals. Long range goals are to determine: 1) mechanism of peptide activation, 2) processes responsible for thrombocytopenia, 3) relationship between thrombocytopenia and pulmonary thrombosis, 4) role of pulmonary endothelium and leukocytes in pulmonary thrombus formation, 5) relationship between pulmonary thrombosis, cardiac failure and hepatomegaly, and 6) the correlations between composition, structure, and activity of the peptides. The severe peptide-induced thrombocytopenia (less than 5% of baseline value) begins approximately 30 minutes after peptide injection, is apparently complete in a few minutes, and is sparing of leukocytes. Initial specific aims are to determine the kinetics of thrombocytopenia, pulmonary thrombosis and hepatomegaly using sequential platelet counts and histopathological examination. Then the site and kinetics of activation and clearance of the peptide or its metabolic product(s) will be followed in vivo and in liver cell cultures. The time courses and the sites of platelet aggregation, sequestration, or destruction will be evaluated by histopathology, isotopic and fluorescence labeling of platelets, platelet aggregometry and electron microscopy. The role of the arachidonic acid cascade, in particular the lipoxygenase sequence, will be studied by pharmacological manipulation and biochemical analysis using radioimmunoassay and HPLC. The contribution of pulmonary endothelium and leukocytes to thrombocytopenia and pulmonary thrombosis will be evaluated with endothelial cell cultures, platelet aggregometry and isotope-labeled platelets. The chemical and structural features of the peptides responsible for their specificity and action will be assessed with a series of naturally-occurring peptides of varied composition.
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