Inhibition of 5-lipoxygenase pathway attenuates acute liver failure by inhibiting macrophage activation.

Abstract

This study aimed to investigate the role of 5-lipoxygenase (5-LO) in acute liver failure (ALF) and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor), 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT), aspartate transaminase (AST), total bilirubin (Tbil), and tumor necrosis factor- (TNF-) α . Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF- α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

• Authors: Lu Li, Yi-Rong Liu, Shan Gao, Jun-Feng Li, Shan-Shan Li, Dan-Dan Zhang, Shuang Liu, Li Bai, Su-Jun Zheng, Zhong-Ping Duan, Min Qi, Yu Chen
• Journal: Journal of immunology research (J Immunol Res) Vol. 2014 Pg. 697560 ( 2014) ISSN: 2314-7156 [Electronic] Egypt
• PMID: 24987711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• Lipopolysaccharides
• Lipoxygenase Inhibitors
• Tumor Necrosis Factor-alpha
• 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone
• Arachidonate 5-Lipoxygenase

Topics

• Animals
• Arachidonate 5-Lipoxygenase (genetics, metabolism)
• Benzoquinones (administration & dosage, pharmacology)
• Disease Models, Animal
• Gene Expression
• Lipopolysaccharides (adverse effects, immunology)
• Lipoxygenase Inhibitors (administration & dosage, pharmacology)
• Liver Failure, Acute (immunology, metabolism, mortality, pathology)
• Macrophage Activation (drug effects, immunology)
• Macrophages (drug effects, immunology, metabolism, ultrastructure)
• Male
• Necrosis (chemically induced, pathology)
• Rats
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (blood, metabolism)