Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model

M. Maglione, R. Oberhuber, B. Cardini, K. Watschinger, M. Hermann, P. Obrist, P. Hengster, W. Mark, S. Schneeberger, G. Werner-Felmayer, J. Pratschke, R. Margreiter, E. R. Werner, G. Brandacher

Research output: Contribution to journalArticlepeer-review

Abstract

Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 μM H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation.

Original languageEnglish (US)
Pages (from-to)2231-2240
Number of pages10
JournalAmerican Journal of Transplantation
Volume10
Issue number10
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • Animal models
  • donor preconditioning
  • endothelial dysfunction
  • endothelial nitric oxide synthase
  • ischemia/reperfusion injury
  • mice
  • nitric oxide
  • oxidative stress
  • pancreas transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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