Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Abstract

Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H 2 S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine clyase (CSE, an enzyme produces H 2 S) 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 DLpropargylglycine 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-a (TNF-a)-induced cell death without affecting LPS-induced TNF-a 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 Aktand 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. Antioxid. Redox Signal. 20,[204][205][206][207][208][209][210][211][212][213][214][215][216]

Hydrogen Sulfide and Neuroinflammation

“…In addition, H 2 S donors have been shown to exert potent anti-inflammatory effects in other forms of inflammatory pathologies Shirozu et al 2013;Tokuda et al 2012;Whiteman et al 2009). While these beneficial effects had been speculated to reflect general antioxidant and anti-inflammatory actions of H 2 S, numerous studies have failed to reveal a beneficial effect of antioxidants in PD.…”

Farnesyltransferase Inhibitor, Tipifarnib, Prevents Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

“…Plasma alanine aminotransferase (ALT) and aspartic aminotransferase (AST) levels, as markers of hepatic damage, at baseline and 5 h after GalN/LPS injections were measured using an Infinity™ ALT and AST assay regent (Thermo Fisher Scientific Inc., Middletown, VA) as previously reported (10). …”

“…Peritoneal macrophages were prepared from un-stimulated naïve mice, as previously described (10). The cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FCS, 100U/ml penicillin and streptomycin, and 2 mM glutamine.…”

Medical uses of Sodium thiosulfate

“…Recently STS was demonstrated to function as an anti-inflammatory agent 11 . For example, in acute liver failure induced in mice by lipopolysaccharide (LPS) or LPS/D-Galactosamine, the survival rate was improved by hydrogen sulfide and STS 12,13 . This at least is partially due to their anti-oxidative functions.…”