Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor

Taihei Ito, Keiko Omori, Jeffrey Rawson, Ivan Todorov, Sadaki Asari, Akio Kuroda, Jonathan Shintaku, Shin Itakura, Kevin Ferreri, Fouad Kandeel, Yoko Mullen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND.: The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) before cold preservation. METHODS.: Pancreata removed from Beagle dogs were infused with University of Wisconsin solution containing the p38IH, SB203580, and Pefabloc (n=6) or vehicle (dimethyl sulfoxide and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20 to 22 hr, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. RESULTS.: p38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2134±297 vs. 1477±145 IEQ/g or 65,012±9385 vs. 45,700±5103 IEQ/pancreas; P<0.05). Apoptotic β-cell percentages assessed by laser scanning cytometry were lower in p38IH-treated than the controls (44%±9.4% vs. 61.6%±4.8%, P<0.05). Tumor necrosis factor-α expression assessed by real-time reverse transcription polymerase chain reaction was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic versus four of five dogs that received untreated islets. Plasma C-peptide levels after glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) versus untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, P<0.05). CONCLUSIONS.: Infusion of pancreata with University of Wisconsin solution containing p38IH through the duct before preservation suppresses cytokine release, prevents β-cell apoptosis, and improves islet yield significantly with no adverse effect on islet function after transplantation. p38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.

Original languageEnglish
Pages (from-to)321-329
Number of pages9
JournalTransplantation
Volume86
Issue number2
DOIs
Publication statusPublished - 27-07-2008

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Canidae
Pancreas
Tissue Donors
Dogs
Laser Scanning Cytometry
Transplantation
Cytokines
Cold Ischemia
C-Peptide
Pancreatic Ducts
p38 Mitogen-Activated Protein Kinases
Dimethyl Sulfoxide
Reperfusion Injury
Glucagon
Reverse Transcription
Tumor Necrosis Factor-alpha
Apoptosis
Glucose
Polymerase Chain Reaction
Control Groups

All Science Journal Classification (ASJC) codes

  • Transplantation
  • Immunology

Cite this

Ito, T., Omori, K., Rawson, J., Todorov, I., Asari, S., Kuroda, A., ... Mullen, Y. (2008). Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor. Transplantation, 86(2), 321-329. https://doi.org/10.1097/TP.0b013e31817ef6c9
Ito, Taihei ; Omori, Keiko ; Rawson, Jeffrey ; Todorov, Ivan ; Asari, Sadaki ; Kuroda, Akio ; Shintaku, Jonathan ; Itakura, Shin ; Ferreri, Kevin ; Kandeel, Fouad ; Mullen, Yoko. / Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor. In: Transplantation. 2008 ; Vol. 86, No. 2. pp. 321-329.
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abstract = "BACKGROUND.: The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) before cold preservation. METHODS.: Pancreata removed from Beagle dogs were infused with University of Wisconsin solution containing the p38IH, SB203580, and Pefabloc (n=6) or vehicle (dimethyl sulfoxide and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20 to 22 hr, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. RESULTS.: p38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2134±297 vs. 1477±145 IEQ/g or 65,012±9385 vs. 45,700±5103 IEQ/pancreas; P<0.05). Apoptotic β-cell percentages assessed by laser scanning cytometry were lower in p38IH-treated than the controls (44{\%}±9.4{\%} vs. 61.6{\%}±4.8{\%}, P<0.05). Tumor necrosis factor-α expression assessed by real-time reverse transcription polymerase chain reaction was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic versus four of five dogs that received untreated islets. Plasma C-peptide levels after glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) versus untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, P<0.05). CONCLUSIONS.: Infusion of pancreata with University of Wisconsin solution containing p38IH through the duct before preservation suppresses cytokine release, prevents β-cell apoptosis, and improves islet yield significantly with no adverse effect on islet function after transplantation. p38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.",
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Ito, T, Omori, K, Rawson, J, Todorov, I, Asari, S, Kuroda, A, Shintaku, J, Itakura, S, Ferreri, K, Kandeel, F & Mullen, Y 2008, 'Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor', Transplantation, vol. 86, no. 2, pp. 321-329. https://doi.org/10.1097/TP.0b013e31817ef6c9

Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor. / Ito, Taihei; Omori, Keiko; Rawson, Jeffrey; Todorov, Ivan; Asari, Sadaki; Kuroda, Akio; Shintaku, Jonathan; Itakura, Shin; Ferreri, Kevin; Kandeel, Fouad; Mullen, Yoko.

In: Transplantation, Vol. 86, No. 2, 27.07.2008, p. 321-329.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Improvement of canine islet yield by donor pancreas infusion with a p38MAPK inhibitor

AU - Ito, Taihei

AU - Omori, Keiko

AU - Rawson, Jeffrey

AU - Todorov, Ivan

AU - Asari, Sadaki

AU - Kuroda, Akio

AU - Shintaku, Jonathan

AU - Itakura, Shin

AU - Ferreri, Kevin

AU - Kandeel, Fouad

AU - Mullen, Yoko

PY - 2008/7/27

Y1 - 2008/7/27

N2 - BACKGROUND.: The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) before cold preservation. METHODS.: Pancreata removed from Beagle dogs were infused with University of Wisconsin solution containing the p38IH, SB203580, and Pefabloc (n=6) or vehicle (dimethyl sulfoxide and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20 to 22 hr, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. RESULTS.: p38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2134±297 vs. 1477±145 IEQ/g or 65,012±9385 vs. 45,700±5103 IEQ/pancreas; P<0.05). Apoptotic β-cell percentages assessed by laser scanning cytometry were lower in p38IH-treated than the controls (44%±9.4% vs. 61.6%±4.8%, P<0.05). Tumor necrosis factor-α expression assessed by real-time reverse transcription polymerase chain reaction was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic versus four of five dogs that received untreated islets. Plasma C-peptide levels after glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) versus untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, P<0.05). CONCLUSIONS.: Infusion of pancreata with University of Wisconsin solution containing p38IH through the duct before preservation suppresses cytokine release, prevents β-cell apoptosis, and improves islet yield significantly with no adverse effect on islet function after transplantation. p38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.

AB - BACKGROUND.: The activation of p38 mitogen-activated protein kinases (MAPK) is implicated in cold ischemia-reperfusion injury of donor organs. The islet isolation process, from pancreas procurement through islet collection, may activate p38MAPK leading to cytokine release and islet damage. This damage may be prevented by treating pancreata with a p38MAPK inhibitor (p38IH) before cold preservation. METHODS.: Pancreata removed from Beagle dogs were infused with University of Wisconsin solution containing the p38IH, SB203580, and Pefabloc (n=6) or vehicle (dimethyl sulfoxide and Pefabloc) alone (n=7), through the pancreatic duct and preserved using the two-layer method. After 20 to 22 hr, islets were isolated and 3000 IEQ/kg were autotransplanted into the corresponding dog to monitor glucose metabolism. RESULTS.: p38IH-treated pancreata yielded significantly more islets than control pancreata (IEQ/g: 2134±297 vs. 1477±145 IEQ/g or 65,012±9385 vs. 45,700±5103 IEQ/pancreas; P<0.05). Apoptotic β-cell percentages assessed by laser scanning cytometry were lower in p38IH-treated than the controls (44%±9.4% vs. 61.6%±4.8%, P<0.05). Tumor necrosis factor-α expression assessed by real-time reverse transcription polymerase chain reaction was significantly lower in the p38IH-treated group than controls. All dogs (3000 IEQ/kg) transplanted with p38IH-treated islets (n=5) became euglycemic versus four of five dogs that received untreated islets. Plasma C-peptide levels after glucagon challenge were higher in animals receiving p38IH-treated islets (n=5) versus untreated islets (n=4) (0.40±0.78 vs. 0.21±0.05 ng/mL, P<0.05). CONCLUSIONS.: Infusion of pancreata with University of Wisconsin solution containing p38IH through the duct before preservation suppresses cytokine release, prevents β-cell apoptosis, and improves islet yield significantly with no adverse effect on islet function after transplantation. p38IH treatment of human pancreata may improve islet yield for use in clinical transplantation.

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