BACKGROUND: Ischemia-reperfusion (I/R) injury is a prime inflammatory factor in the dysfunction of orthotopic liver transplants. Interleukin (IL)-13 suppresses macrophage production of proinflammatory mediators. This study explores the effects of adenovirus (Ad)-based IL-13 gene transfer in rat models of hepatic I/R injury. METHODS: The authors used a model of warm in situ ischemia followed by reperfusion, and ex vivo cold ischemia followed by transplantation. RESULTS: In a model of warm in situ ischemia followed by reperfusion, Ad-based IL-13 significantly diminished hepatocellular injury, assessed by serum glutamic oxaloacetic transaminase (SGOT) levels, as compared with Ad-based beta-galactosidase (gal)-treated livers. In a model of ex vivo cold ischemia followed by transplantation, the survival of liver grafts increased from 50% in Ad-beta-gal untreated controls to 100% after Ad-IL-13 gene therapy. This beneficial effect correlated with improved liver function (SGOT levels), preservation of hepatic histologic integrity and architecture (Suzuki criteria), and depression of neutrophil infiltration (myeloperoxidase assay). Ad-IL-13 diminished activation of macrophage-neutrophil-associated tumor necrosis factor-alpha, macrophage inflammatory protein-2, and endothelial-dependent E-selectin, but increased type 2 IL-4 and IL-13 expression. CONCLUSIONS: This study documents striking cytoprotective effects of virally induced IL-13 against hepatic I/R injury in two clinically relevant rat models of hepatic I/R injury. These data provide the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of warm or cold ischemia, or both.
BACKGROUND:Ischemia-reperfusion (I/R) injury is a prime inflammatory factor in the dysfunction of orthotopic liver transplants. Interleukin (IL)-13 suppresses macrophage production of proinflammatory mediators. This study explores the effects of adenovirus (Ad)-based IL-13 gene transfer in rat models of hepatic I/R injury. METHODS: The authors used a model of warm in situ ischemia followed by reperfusion, and ex vivo cold ischemia followed by transplantation. RESULTS: In a model of warm in situ ischemia followed by reperfusion, Ad-based IL-13 significantly diminished hepatocellular injury, assessed by serum glutamic oxaloacetic transaminase (SGOT) levels, as compared with Ad-based beta-galactosidase (gal)-treated livers. In a model of ex vivo cold ischemia followed by transplantation, the survival of liver grafts increased from 50% in Ad-beta-gal untreated controls to 100% after Ad-IL-13 gene therapy. This beneficial effect correlated with improved liver function (SGOT levels), preservation of hepatic histologic integrity and architecture (Suzuki criteria), and depression of neutrophil infiltration (myeloperoxidase assay). Ad-IL-13 diminished activation of macrophage-neutrophil-associated tumor necrosis factor-alpha, macrophage inflammatory protein-2, and endothelial-dependent E-selectin, but increased type 2 IL-4 and IL-13 expression. CONCLUSIONS: This study documents striking cytoprotective effects of virally induced IL-13 against hepatic I/R injury in two clinically relevant rat models of hepatic I/R injury. These data provide the rationale for novel therapeutic approaches to maximize the organ donor pool through the safer use of liver transplants despite prolonged periods of warm or cold ischemia, or both.
Authors: Bibo Ke; Xiu-Da Shen; Feng Gao; Seiichiro Tsuchihashi; Douglas G Farmer; David Briscoe; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Transplantation Date: 2005-05-15 Impact factor: 4.939
Authors: Douglas G Farmer; Bibo Ke; Xiu-Da Shen; Fady M Kaldas; Feng Gao; Melissa J Watson; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Transplantation Date: 2011-04-15 Impact factor: 4.939
Authors: Bibo Ke; Xiu-Da Shen; Feng Gao; Ronald W Busuttil; Pedro R Löwenstein; Maria G Castro; Jerzy W Kupiec-Weglinski Journal: Mol Ther Date: 2004-01 Impact factor: 11.454