P3 Inhaled hydrogen sulfide protects mice against Gal/LPS-induced acute liver failure

Abstract

Introduction Acute liver failure is a fatal syndrome attributed to massive hepatocyte apoptosis that is resistant to conventional medical therapies.Consequently, liver transplantation is required in many cases.An experimental liver failure model induced by galactosamine (Gal) and lipopolysaccharide (LPS) mimics clinical fulminant hepatitis.In this model, LPS stimulates macrophages to release TNF α , which induces apoptosis in Gal-sensitized hepatocytes, resulting in liver failure.Hydrogen sulfide (H 2 S), which is an endogeneously-produced gaseous signaling molecule, has anti-apoptotic as well as anti-inflammatory properties.Previously, we reported that H 2 S attenuates liver dysfunction arising from LPS-induced systemic inflammation.It has also been reported that H 2 S reduces hepatic ischemia/reperfusion injury by inhibition of apoptosis in the liver.However, whether H 2 S exerts hepatoprotective effects against acute liver failure, in which both inflammatory responses and apoptosis play pivotal roles, remains unknown.Here, we examined the impact of inhaled H 2 S on acute liver failure in mice induced by Gal and LPS. Methods Mice were challenged with saline or combination of Gal (700 mg/kg) and LPS (10 μg/kg) intraperitoneally and thereafter randomized to breathe either air alone or air supplemented with H 2 S (80 ppm) for 6 h. Results Mice that breathed air after Gal/LPS challenge showed poor survival rate (13%) and marked increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma.In contrast, H 2 S inhalation for 6 h after challenge markedly improved survival (60%, p 2 S suppressed TNF α in plasma at 1 h after Gal/LPS challenge.Mice that breathed air after Gal/LPS challenge exhibited activation of caspase 3, 8, and 9 in the liver, whereas H 2 S breathing inhibited activation of caspase 3, 8, and 9, suggesting inhaled H 2 S after Gal/LPS challenge suppressed both extrinsic and intrinsic pathways of caspase-dependent apoptosis in the liver ( Fig.1 ).Gal/LPS challenge increased phosphorylated STAT3 transcription factor.H 2 S inhalation after Gal/LPS challenge further augmented phosphorylation of STAT3 compared to air alone ( Fig.2 ).The protective effects of H 2 S inhalation after Gal/LPS challenge were associated with upregulation of gene expression of anti-inflammatory IL-10, which stimulates STAT3 phosphorylation, in the liver.These results suggest that inhaled H 2 S contributes to survival of mice in acute liver failure at least in part through activation of IL-10/STAT3 pathway. Conclusion These results suggest that H 2 S protects mice from acute liver failure at least in part by inhibition of caspase activation and by augmentation of IL-10/STAT3 signaling pathway in the liver.