Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

Abstract

Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co‐factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham‐operated controls, donor BD resulted in intragraft inflammation reflected by induced IL‐1ß, IL‐6, VCAM‐1, and P‐selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4‐treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non‐BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD‐associated injury after transplantation.

Donor brain death leads to differential immune activation in solid organs but does not accelerate ischaemia-reperfusion injury

“…It has been demonstrated by us and others that BD itself disturbs the microcirculation in peripheral organs independent of systemic haemodynamic decline . Based on our findings obtained in two syngeneic transplantation models, we conclude that donor BD does not accelerate IRI‐related inflammation in the early post‐transplantation period.…”

Follicular growth after xenotransplantation of cryopreserved/thawed human ovarian tissue in SCID mice: dynamics and molecular aspects

“…Mice were anesthetized with 0.1 mg/g body weight ketamine hydrochloride (Ketasol, Gräub, Ogris Pharma, Austria) and 0.015 mg/g body weight of xylazine (Xylasol, Ani Medica Ogris Pharma, Austria) intraperitoneally [44]. The average body weight was 16.66 g and ranged from 14.50 to 18.40 g. The surgery was performed on a 37 °C warming plate for animal surgery (Vettech, UK).…”

Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice

“…Interestingly, our results showed for the first time that the acute BH4 treatment administered during this late phase of inflammation greatly attenuated the increased expression of pro-inflammatory cytokines that persisted 24h after LPS challenge. Such a down regulation of pro-inflammatory cytokines has been described after BH4 treatment in a murine model of pancreas transplantation (Oberhuber et al 2015). This was associated to a gain in the cell viability of the transplant and to a prolonged recipient survival.…”