Cytoprotective and antiapoptotic effects of IL-13 in hepatic cold ischemia/reperfusion injury are heme oxygenase-1 dependent.
Liver injury caused by ischemia/reperfusion (I/R) insult represents the major problem following orthotopic liver transplantation (OLT). I/R damage has been linked to Th1-like cytokine producers. This study evaluates putative cytoprotective effects/mechanisms of Th2-type IL-13 gene transfer. IL-13 overexpression prevented hepatic insult in a rat model of 24 h cold ischemia followed by OLT, as assessed: (i) profoundly decreased hepatocellular damage (sGOT levels), and ameliorated histological signs of I/R injury (Suzuki criteria), consistent with long-term OLT survival; (ii) prevented hepatic apoptosis (TUNEL stains) and up-regulated expression of antiapoptotic (A20, Bcl-2/Bcl-xl)/antioxidant (HO-1) genes. However, inhibition of HO-1 with tin protoporphyrin reversed cytoprotective/antiapoptotic effects of IL-13. In conclusion, cytoprotection rendered by virally induced IL-13 against hepatic I/R injury in this clinically relevant rat hepatic cold I/R injury model was accomplished via decreased apoptosis and induction of antiapoptotic/antioxidant molecules. HO-1 neutralization studies suggest that HO-1 represents one of putative IL-13 downstream effectors. This study provides the rationale for novel approaches to maximize organ donor pool through the safer use of OLTs despite prolonged periods of cold ischemia.
Ke
Bibo
B
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Shen
Xiu-Da
XD
Lassman
Charles R
CR
Gao
Feng
F
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D051547:Heme Oxygenase-1; D020287:In Situ Nick-End Labeling; D018793:Interleukin-13 / Q000627:therapeutic use*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation; D016031:Liver Transplantation / Q000473:pathology* / Q000502:physiology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009926:Organ Preservation / Q000379:methods*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D013534:Survival
D004791:Enzyme Inhibitors; D018793:Interleukin-13; D008665:Metalloporphyrins; D011524:Protoporphyrins; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001219:Aspartate Aminotransferases