Myocardial ischemia reperfusion injury, a consequence of organ preservation and implantation, adversely impacts both early and late outcomes after heart transplantation. As heart failure is highly prevalent among the veteran population, this area of investigation is of very high significance. While neutrophils are critical mediators of myocardial ischemia reperfusion injury, little is known about their trafficking and activation requirements during this form of sterile inflammation. Utilizing our newly developed technique of intravital imaging of beating mouse hearts, we have uncovered a role for innate immune molecules in donor hearts for entry of neutrophils into the graft tissue of freshly reperfused cardiac transplants. This application proposes to study mechanisms for neutrophil recruitment during myocardial ischemia reperfusion injury of heart grafts and will allow for the development of new therapeutic strategies.
Large numbers of veterans suffer from end-stage heart failure, for which cardiac transplantation remains of the most effective therapies. Myocardial inflammation secondary to ischemia reperfusion injury, however, negatively impacts the success of this procedure. The pathways that lead to ischemia reperfusion injury-mediated myocardial inflammation after heart transplantation are yet to be fully elucidated. This application will examine innate immune pathways that lead to inflammation after cardiac transplantation in mice. The proposed experiments will yield novel information that could lead to new therapies to reduce inflammation within hearts that are subjected to ischemia and reperfusion.