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

被引:10
|
作者
Wimborne, Hereward J. [1 ,2 ]
Takemoto, Kenji [1 ,2 ]
Woster, Patrick M. [2 ]
Rockey, Don C. [3 ]
Lemasters, John J. [1 ,2 ,4 ,5 ]
Zhong, Zhi [1 ,2 ]
机构
[1] Med Univ South Carolina, Ctr Cell Death Injury & Regenerat, Charleston, SC 29425 USA
[2] Med Univ South Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA
[3] Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA
[4] Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA
[5] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA
基金
美国国家卫生研究院;
关键词
4-Hydroxynonenal; Alda-1; Aldehyde dehydrogenase-2; Aldehydes; Fibrosis; Hepatic stellate cells; Inflammation; Macrophages; Osteopontin; Oxidative stress; ISCHEMIA-REPERFUSION INJURY; HEPATIC STELLATE CELLS; INDUCED LIVER FIBROSIS; CYTOCHROME-C-OXIDASE; OXIDATIVE STRESS; OSTEOPONTIN; RAT; CHOLESTASIS; DISEASE; PATHOGENESIS;
D O I
10.1016/j.freeradbiomed.2019.09.026
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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: C57B1/6J 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% M 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 alpha-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.
引用
收藏
页码:136 / 145
页数:10
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