TY - JOUR
T1 - Prolonged Cold Ischemia Time Results in Local and Remote Organ Dysfunction in a Murine Model of Vascularized Composite Transplantation
AU - Datta, N.
AU - Devaney, S. G.
AU - Busuttil, R. W.
AU - Azari, K.
AU - Kupiec-Weglinski, J. W.
N1 - Funding Information:
This study was funded by the Department of Defense AFIRM II (WFUHS 441042 CTA-12), a grant from the H&H Lee Surgical Research Scholars Program, and The Dumont Research Foundation. We thank Dr Gerald Brandacher and his laboratory colleagues at Johns Hopkins University School of Medicine for invaluable assistance and advice.
Publisher Copyright:
© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - basic (laboratory) research/science
KW - immunobiology
KW - organ perfusion and preservation
KW - organ procurement and allocation
KW - tissue injury and repair
KW - vascularized composite and reconstructive transplantation
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U2 - 10.1111/ajt.14290
DO - 10.1111/ajt.14290
M3 - Article
C2 - 28371289
AN - SCOPUS:85019036499
SN - 1600-6135
VL - 17
SP - 2572
EP - 2579
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 10
ER -