World journal of gastroenterology · 2012
Zinc finger protein A20 protects rats against chronic liver allograft dysfunction.
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Yang Jie, Xu Ming-Qing, Yan Lu-Nan, Chen Xiao-Bo, Liu Jiao
Аннотация
AIM: To investigate the effect of zinc finger protein A20 on chronic liver allograft dysfunction in rats.
METHODS: Allogeneic liver transplantation from DA rats to Lewis rats was performed. Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer administered intravenously every 10 d starting from POD 10. The recipient rats were injected with physiological saline, rAdEasy-A20 (1 × 10(9) pfu/30 g weight) or rAdEasy (1 × 10(9) pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10. Liver tissue samples were harvested on POD 30 and POD 60.
RESULTS: Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis. A20 overexpression ameliorated the effects on liver function, attenuated liver allograft fibrosis and prolonged the survival of the recipient rats. Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF)-β1, interleukin-1β, caspase-8, CD40, CD40L, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin. A20 treatment suppressed liver cell apoptosis and inhibited nuclear factor-κB activation of Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF-β1 in HSCs.
CONCLUSION: A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs, LSECs and HSCs.
METHODS: Allogeneic liver transplantation from DA rats to Lewis rats was performed. Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer administered intravenously every 10 d starting from POD 10. The recipient rats were injected with physiological saline, rAdEasy-A20 (1 × 10(9) pfu/30 g weight) or rAdEasy (1 × 10(9) pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10. Liver tissue samples were harvested on POD 30 and POD 60.
RESULTS: Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis. A20 overexpression ameliorated the effects on liver function, attenuated liver allograft fibrosis and prolonged the survival of the recipient rats. Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF)-β1, interleukin-1β, caspase-8, CD40, CD40L, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin. A20 treatment suppressed liver cell apoptosis and inhibited nuclear factor-κB activation of Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF-β1 in HSCs.
CONCLUSION: A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs, LSECs and HSCs.
Предметные рубрики MeSH
AdenoviridaeAnimalsApoptosisBiomarkersCells, CulturedChronic DiseaseCysteine EndopeptidasesCytokinesDisease Models, AnimalEndothelial CellsGene Expression RegulationGene Transfer TechniquesGenetic TherapyGenetic VectorsHepatic Stellate CellsImmunosuppressive AgentsInflammation MediatorsIntracellular Signaling Peptides and ProteinsKupffer CellsLiverLiver CirrhosisLiver DiseasesLiver TransplantationMaleNF-kappa BRatsRats, Inbred LewTacrolimusTime FactorsTransforming Growth Factor beta1Tumor Necrosis Factor alpha-Induced Protein 3