Research Project
2233638
During cardiopulmonary bypass, plasma factor XII is converted to active XIIa by contact with the surfaces of the bypass circuit, initiating a process which results in massive activation of the plasma proteases of the contact system. Products of contact activation include bradykinin from the kallikrein-kinin system and the neutrophil activators XIIa, kallikrein and complement factor C5a. Neutrophil activation can result in neutrophil- mediated lung damage and dysfunction, a significant cause of post-bypass morbidity. The goal of this research is to discover a potent protein inhibitor of human factor XIIa which can be used to prevent activation of the contact system during extracorporeal circulation in order to attenuate post-bypass pulmonary injury. Phagemid libraries which display variants of the Kunitz protease inhibitor domain (KPI) of human protease nexin-2/amyloid beta-protein precursor will be selected with immobilized human factor XIIa to identify KPI mutants which inhibit human-factor XIIa with high potency. In the Phase II time period, a potent KPI-derived XIIa inhibitor will be tested in vivo for its ability to inhibit the contact activation system and reduce neutrophil- mediated lung damage in an animal model of cardiopulmonary bypass. PROPOSED COMMERCIAL APPLICATION: A potent protein inhibitor of factor 'ala would be used prophylactically during surgeries requiring cardiopulmonary bypass to inhibit activation of the plasma proteases of the contact system. Inhibition of contact activation should reduce neutrophil-mediated pulmonary injury which can contribute to post-bypass morbidity.
