Antioxidants & redox signaling · 2013
Cystathionine γ-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Shirozu Kazuhiro, Tokuda Kentaro, Marutani Eizo, Lefer David, Wang Rui, Ichinose Fumito
Аннотация
AIMS: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS).
RESULTS: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice.
INNOVATION: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver.
CONCLUSION: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms.
RESULTS: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice.
INNOVATION: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver.
CONCLUSION: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms.
Предметные рубрики MeSH
AnimalsApoptosisCaspase 3Cell SurvivalCystathionine gamma-LyaseDisease Models, AnimalGalactosamineGene Expression RegulationHepatocytesJNK Mitogen-Activated Protein KinasesLipopolysaccharidesLiverLiver Failure, AcuteMacrophages, PeritonealMaleMembrane Potential, MitochondrialMiceModels, BiologicalNF-E2-Related Factor 2Oxidation-ReductionPhosphorylationPoly(ADP-ribose) PolymerasesProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-bcl-2Quinone ReductasesSulfidesThiosulfatesTumor Necrosis Factor-alpha