Aldehyde dehydrogenase-2 activation by Alda-1 decreases necrosis and fibrosis after bile duct ligation in mice.

BACKGROUND AND AIM: Liver fibrosis is a leading cause of mortality worldwide. Oxidative stress is a key component in the pathogenesis of liver fibrosis. We investigated the role of aldehyde formation resulting from lipid peroxidation in cholestatic liver injury and fibrosis. METHODS: C57Bl/6J mice underwent bile duct ligation (BDL) or sham operation. One hour after surgery and daily thereafter, animals were given Alda-1 (20 mg/kg, s.c.), an aldehyde dehydrogenase-2 activator, or equivalent volume of vehicle. Blood and livers were collected after 3 and 14 days. RESULTS: Serum alanine aminotransferase (ALT) increased from 39.8 U/L after sham operation to 537 U/L 3 days after BDL, which Alda-1 decreased to 281 U/L. Biliary infarcts with a periportal distribution developed with an area of 7.8% at 14 days after BDL versus 0% area after sham operation. Alda-1 treatment with BDL decreased biliary infarcts to 1.9%. Fibrosis detected by picrosirius red staining increased from 1.6% area in sham to 7.3% after BDL, which decreased to 3.8% with Alda-1. Alda-1 suppression of fibrosis was additionally confirmed by second harmonic generation microscopy. After BDL, collagen-I mRNA increased 12-fold compared to sham, which decreased to 6-fold after Alda-1 treatment. Smooth muscle α-actin expression in the liver, a marker of activated stellate cells, increased from 1% area in sham to 18.7% after BDL, which decreased to 5.3% with Alda-1. CD68-positive macrophages increased from 33.4 cells/field in sham to 134.5 cells/field after BDL, which decreased to 64.9 cells/field with Alda-1. Lastly, 4-hydroxynonenal adduct (4-HNE) immunofluorescence increased from 2.5% area in sham to 14.1% after BDL. Alda-1 treatment decreased 4-HNE to 2.2%. CONCLUSION: Accelerated aldehyde degradation by Alda-1 decreases BDL-induced liver necrosis, inflammation, and fibrosis, implying that aldehydes play an important role in the pathogenesis of cholestatic liver injury and fibrosis.