Brain death (BD) and ischemia reperfusion injury (IRI) are unavoidable consequences of heart transplantation. Brain death produces profound physiologic derangements and the systemic effects of this central injury, although little studied, are known to contribute to peripheral organ ischemia, the upregulation of adhesion molecules, cytokine expression and leukocyte accumulation within the donor heart. Brain death induced inflammation in the donor also renders the heart more susceptible to IRI in the recipient, and there is evidence to indicate that both of these injurious events have negative long-term consequences with regard to allograft survival. Our working hypothesis is that complement plays a central role in causing myocardial BD- induced inflammation and injury, and enhances IRI in the recipient. We propose that a complement inhibitory strategy applied to the donor (in addition to the recipient) will provide protection from inflammation and injury, and as a consequence, will improve long-term graft survival due to decreased graft immunogenicity and host alloresponsiveness. We propose to utilize relevant mouse models to determine the role of complement in myocardial brain death induced injury (BDI) and in IRI following heart transplantation. Our investigations will focus on complement effector mechanisms and in vivo interactions between complement and P-selectin, an adhesion molecule that is strongly implicated in myocardial IRI and that is expressed in the heart following BD. We further propose to develop novel therapeutic strategies based on targeted complement inhibition and P-selectin antagonism, and to characterize the inhibitors in our newly developed mouse model of heart transplantation incorporating donor BD. We specifically propose to: 1. Determine complement effector mechanism(s) involved in myocardial injury following brain death 2. Develop and characterize novel therapeutic strategies based on P-selectin targeted complement inhibition and P-selectin antagonism and, 3. Determine the effect of anti-complement therapy in the BD donor, the recipient, or both, on the severity of myocardial IRI after heart transplantation and on the development of an alloimmune response and acute rejection of the graft. ? ? ?
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