Rho-kinase as a novel gene therapeutic target in treatment of cold ischemia/reperfusion-induced acute lethal liver injury: effect on hepatocellular NADPH oxidase system
| Autor: | Yuji Soejima, Mitsuo Shimada, Akinobu Taketomi, Satoko Shiotani, Tomoharu Yoshizumi, Kohji Hashimoto, Hiroaki Shimokawa, Yoshihiko Maehara |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Genetic Vectors Gene Expression Biology Pharmacology Adenoviridae chemistry.chemical_compound Transduction Genetic In vivo Rats Inbred BN Genetics medicine Animals Enzyme Inhibitors Molecular Biology Rho-associated protein kinase Liver injury chemistry.chemical_classification rho-Associated Kinases Reactive oxygen species NADPH oxidase Tumor Necrosis Factor-alpha Graft Survival Acetophenones NADPH Oxidases Genetic Therapy medicine.disease Liver Transplantation Rats Cold Temperature Transplantation chemistry NAD(P)H oxidase Reperfusion Injury Acute Disease Models Animal Immunology Apocynin Hepatocytes biology.protein Molecular Medicine Reactive Oxygen Species Interleukin-1 Liver Circulation |
| Zdroj: | Gene Therapy. 14:1425-1433 |
| ISSN: | 1476-5462 0969-7128 |
| Popis: | In the transplant surgery, reactive oxygen species (ROS) from the reperfused tissue cause ischemia-reperfusion injury, resulting in the primary graft failure. We have recently reported that Rho-kinase, an effecter of the small GTPase Rho, plays an important role in the ROS production in the hyperacute phase of reperfusion; however, the sources and mechanisms of the ROS production remain to be elucidated. The aim of this study was to investigate the source of ROS production with a special reference to Rho-kinase to develop a new strategy against ischemia-reperfusion injury. In an in vivo rat model of liver transplantation, Kupffer cells in the graft were depleted using liposome-encapsulated dichloromethylene diphosphonate to examine the source of ROS production. The effect of adenoviral-mediated overexpression of a dominant-negative Rho-kinase (AdDNRhoK) in hepatocytes in the graft was also examined. Kupffer cells were not involved in the ROS production, whereas the AdDNRhoK transfection to hepatocytes significantly suppressed the ROS production. Furthermore, the ROS production was dose-dependently inhibited by apocynin, an NADPH oxidase inhibitor. Expression of DNRhoK also suppressed the release of pro-inflammatory cytokines, and ameliorated the lethal liver injury with a significant prolongation of the survival. These results suggest that the Rho-kinase-mediated pathway plays a crucial role in the ROS production through NADPH oxidase in hepatocytes during the hyperacute phase of reperfusion in vivo. Thus, Rho-kinase in hepatocytes may be a new therapeutic target for the prevention of primary graft failure in liver transplantation. |
| Databáze: | OpenAIRE |
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