title: Prolonged Cold Ischemia Time Results in Local and Remote Organ Dysfunction in a Murine Model of Vascularized Composite Transplantation.
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.
authors.affiliation: The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
authors.forename: Neha
authors.initials: N
authors.lastname: Datta
authors.affiliation: The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
authors.forename: S G
authors.initials: SG
authors.lastname: Devaney
authors.affiliation: The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
authors.forename: K
authors.initials: K
authors.lastname: Azari
authors.affiliation: The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at University of California, Los Angeles, CA.
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D050377:Cold Ischemia; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006614:Hindlimb; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury; D063986:Vascularized Composite Allotransplantation / Q000009:adverse effects* / Q000379:methods
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators
keywords: basic (laboratory) research/science; immunobiology; organ perfusion and preservation; organ procurement and allocation; tissue injury and repair; vascularized composite and reconstructive transplantation