Liver ischemia contributes to early islet failure following intraportal transplantation: benefits of liver ischemic-preconditioning.
Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic-preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ-induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post-IPIT. Pro-inflammatory cytokines, IL-1beta and IL-6, were significantly increased 3 h after IPIT, while TNF-alpha was elevated for up to 5 days post-IPIT. Caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post-IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre-exposure of the liver to transient ischemia and reperfusion, protected the liver from embolism-induced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.
Yin
D
D
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, Illinois, USA. dyin@uic.edu
Ding
J W
JW
Shen
J
J
Ma
L
L
Hara
M
M
Chong
A S
AS
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004617:Embolism / Q000473:pathology; D006084:Graft Rejection / Q000517:prevention & control*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006943:Hyperglycemia / Q000628:therapy; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control; D019194:Ischemic Preconditioning / Q000379:methods*; D007515:Islets of Langerhans / Q000098:blood supply / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011169:Portal Vein / Q000473:pathology
D016207:Cytokines; D049452:Green Fluorescent Proteins; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases