Brain death (BD) has been shown to exacerbate ischemia reperfusion injury (IRI) in the context of solid organ transplantation and has also been seen as a phenomenon thought to immunologically prime the graft. In several already published studies we were able to demonstrate that tetrahydrobiopterin (BH4), an essential nitric oxide synthase co-factor, diminishes IRI following syngeneic transplantation.
The aim of the present study was in a first step to study the impact of donor BD and IRI in a murine model of syngeneic pancreas transplantation. In a second step we assessed the therapeutic potential of BH4 in this clinically relevant setting.
Analysis of mRNA expression by PCR revealed when compared to sham-operated controls that donor BD resulted in intrapancreatic inammation as reected by induction of IL-1ß, IL-6, VCAM-1, and P-selectin. Similar results were obtained from the analysis of microcirculation after transplantation using fluorescence microscopy. In contrast, pretreatment of the BD donor with BH4 improved microcirculation following reperfusion. Moreover, BD exerted a dramatic impact on cell viability, whereas BH4-treated grafts showed a signicantly greater percentage of viable cells in biopsies taken after reperfusion. Histopathological damage in pancreatic grafts was signicantly more pronounced in organs from BD donors than from sham or non-BD donors. However, BH4 pretreatment signicantly abrogated tissue damage in BD organs. Importantly, donor treatment with BH4 resulted in signicantly prolonged recipient survival.
In conclusion, our data underscore the negative synergistic impact of donor BD and IRI on pancreatic isografts. Moreover, the protective effect of donor pretreatment using BH4 was shown.