Liposomes and Liposome-Annexin Complexes as Adjunctive Therapy for Reperfusion Injury and Hemorrhagic Shock

Previous studies by ourselves and others have shown that natural antibodies recognize epitopes on ischemic tissue and catalyze the initiation and subsequent development of reperfusion injury. Prior to the beginning of these studies, my laboratory had developed monoclonal antibodies from wild type mice that were able to individually transfer the capacity of immunoglobulin deficient Rag-- mice to develop intestinal ischemia-reperfusion injury. We found that these disease-causing natural antibodies recognized either phospholipids or annexin-4. The overall goal of the studies has been to test the concept that a therapeutic which targets the very first steps of reperfusion injury by blocking the effects of antibodies to phospholipids and annexin-4 could be developed. This approach could be used in conjunction with fluids in order to provide a major benefit and substantially decrease the morbidity and mortality associated with battlefield injuries. Studies we performed in collaboration with Dr. George Tsokos at USUHS showed that phospholipid-bearing liposomes that we made protected mice he studied in intestinal ischemia-reperfusion injury models. Our studies at the University of Colorado Health Sciences Center in the past year have focused on developing annexin-4 as a recombinant protein therapeutic and testing the ability of it to block ischemia-reperfusion injury. We report the successful creation of the recombinant protein and positive proof-of-concept data with annexin-4 in intestinal schemia-reperfusion injury.