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Diabetes 53:2559-2568, 2004
© 2004 by the American Diabetes Association, Inc.
Response of Human Islets to Isolation Stress and the Effect of Antioxidant Treatment
1 Department of Pediatrics, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
2 Division of Immunogenetics, Diabetes Institute, Rangos Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
3 Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
The process of human islet isolation triggers a cascade of stressful events in the islets of Langerhans involving activation of apoptosis and necrosis and the production of proinflammatory molecules that negatively influence islet yield and function and may produce detrimental effects after islet transplantation. In this study, we showed that activation of nuclear factor-
B (NF-B) and poly(ADP-ribose) polymerase (PARP), two of the major pathways responsible for cellular responses to stress, already occurs in pancreatic cells during the isolation procedure. NF-B–dependent reactions, such as production and release of interleukin-6 and -8 and macrophage chemoattractant protein 1, were observed days after the isolation procedure in isolated purified islets. Under culture conditions specially designed to mimic isolation stress, islet proinflammatory responses were even more pronounced and correlated with higher islet cell loss and impaired secretory function. Here we present novel evidence that early interventions aimed at reducing oxidative stress of pancreatic cells and islets through the use of the catalytic antioxidant probe AEOL10150 (manganese [III] 5,10,15,20-tetrakis [1,3,-diethyl-2imidazoyl] manganese-porphyrin pentachloride [TDE-2,5-IP]) effectively reduces NF-B binding to DNA, the release of cytokines and chemokines, and PARP activation in islet cells, resulting in higher survival and better insulin release. These findings support the concept that the isolation process predisposes islets to subsequent damage and functional impairment. Blocking oxidative stress can be beneficial in reducing islet vulnerability and can potentially have a significant impact on transplantation outcome.
Address correspondence and reprint requests to Jon D. Piganelli, PhD, Diabetes Institute, Children’s Hospital of Pittsburgh, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213. E-mail: jdp51{at}pitt.edu
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