The aim of the proposed research is to study the pathophysiology and biochemistry of the plasma kinin forming system in man. One pathway for the production of bradykinin is initiated by the activation of Hageman factor and its subsequent transformation to several kallikrein activators. The purification and chemical characterization of prekallikrein activators, as well as the molecular changes which they catalyze in converting prekallikrein to kallikrein, will be explored. The chemical and immunological characteristics of kallikrein will be further defined and its interaction with naturally occurring inhibitors investigated. Activators of prekallikrein will also be sought in normal tissues. A simple biochemical assay for plasma prekallikrein, kallikrein inhibitor and free kallikrein has been developed. Bradykinin release will be simultaneously measured by radioimmunoassay in a collaborative study. These techniques should permit detection of activation of the kallikrein-kinin system in humans with acute allergic reactions, dumping syndrome, transfusion reactions, and liver injury and evaluation of its role in the pathogenesis of these conditions. Animal models such as endotoxin shock in pigs, hyperacute renal allograft rejection in monkeys, and delayed hypersensitivity in guinea pigs will be studied in parallel in order to explore modification of kallikrein activation in these states. These investigations may allow development of new therapeutic approaches to the corresponding human diseases.