Hereward J Wimborne1, Kenji Takemoto1, Patrick M Woster2, Don C Rockey3, John J Lemasters4, Zhi Zhong5. 1. Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, 29425, United States; Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, United States. 2. Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, United States. 3. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, United States. 4. Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, 29425, United States; Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, United States; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, United States. 5. Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, 29425, United States; Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, United States. Electronic address: zhong@musc.edu.
Abstract
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.
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.
Authors: Zhi Zhong; Matthias Froh; Mark Lehnert; Robert Schoonhoven; Liu Yang; Henrik Lind; John J Lemasters; Ronald G Thurman Journal: Am J Physiol Gastrointest Liver Physiol Date: 2003-06-04 Impact factor: 4.052
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Authors: Hasibur Rehman; Qinlong Liu; Yasodha Krishnasamy; Zengdun Shi; Venkat K Ramshesh; Khujista Haque; Rick G Schnellmann; Michael P Murphy; John J Lemasters; Don C Rockey; Zhi Zhong Journal: Int J Physiol Pathophysiol Pharmacol Date: 2016-04-25