Prolonged Cold Ischemia Time Results in Local and Remote Organ Dysfunction in a Murine Model of Vascularized Composite Transplantation

N. Datta, S. G. Devaney, R. W. Busuttil, K. Azari, J. W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Vascularized composite allotransplantation (VCA) is a viable reconstructive option for complex tissue defects. Although grafts with a large muscular component may be uniquely susceptible to ischemia–reperfusion (I/R) syndrome, the safe cold ischemia time in VCA has not been established. We investigated the effects of cold ischemia on innate immune response and recipient survival in a murine orthotopic hindlimb transplantation model. Surprisingly, mice receiving grafts exposed to 6 h or longer of cold storage demonstrated reduced survival and massive elevations in serum creatinine, blood urea nitrogen, and creatine kinase, compared with 1 h of cold storage recipients. This was accompanied by progressive increase in macrophage and neutrophil cell infiltration in muscle biopsy specimens, altered platelet endothelial cell adhesion molecule-1 expression, and ultimate renal injury. Multiplex immunoassay analysis identified 21 cytokines in serum and 18 cytokines in muscle biopsy specimens that are likely essential in the complex response to I/R-triggered injury in VCA. In conclusion, this study, in a mouse model of orthotopic hindlimb transplantation, is the first to document that prolonged cold ischemia triggers progressive I/R injury with vascular endothelial damage and may lead to irrecoverable local and remote organ damage. These experimental findings are important in guiding future therapies for human VCA recipients.

Original languageEnglish (US)
Pages (from-to)2572-2579
Number of pages8
JournalAmerican Journal of Transplantation
Volume17
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

  • basic (laboratory) research/science
  • immunobiology
  • organ perfusion and preservation
  • organ procurement and allocation
  • tissue injury and repair
  • vascularized composite and reconstructive transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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