title: 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.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Toxic Hepatic Diseases, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yi-Rong
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Shan
authors.identifier: 0000-0002-1603-0883
authors.initials: S
authors.lastname: Gao
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Li
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Li
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Su-Jun
authors.initials: SJ
authors.lastname: Zheng
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Zhong-Ping
authors.initials: ZP
authors.lastname: Duan
authors.affiliation: Department of General Medicine, Luoyang Central Hospital, Zhengzhou University, Luoyang 471000, China.
authors.forename: Min
authors.identifier: 0000-0001-8116-9227
authors.initials: M
authors.lastname: Qi
authors.affiliation: Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D017114:Liver Failure, Acute / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D001094:Arachidonate 5-Lipoxygenase