Pretreatment of lipopolysaccharide (LPS) ameliorates D-GalN/LPS induced acute liver failure through TLR4 signaling pathway.
Endotoxin tolerance (ET) is an important phenomenon, which affects inflammation and phagocytosis. Pretreatment with low dose of lipopolysaccharide (LPS) can protect liver injury from various hepatotoxicants such as acetaminophen and pseudomonas aeruginosa exotoxin A. The current study aimed to investigate the protecting mechanisms of endotoxin tolerance in acute liver failure induced by D-galactosamine (D-GalN)/LPS and possible role of toll-like receptors 4 (TLR4) signaling pathway in this phenomenon. Acute liver failure was induced by Injection of D-GalN/LPS. To mimic endotoxin tolerance, male Sprague-Dawley rats were treated with low dose of LPS (0.1 mg/kg once a day intraperitoneally for consecutive five days) before subsequent injection of D-GalN/LPS. Rat survival was determined by survival rate. Liver injury was confirmed by serum biochemical and liver histopathological examination. Inflammatory cytokines were determined by ELISA and nuclear factor-kappa B (NF-κB) (P65), toll-like receptors 4 (TLR4) and Interleukin-1 receptor-associated kinase-1 (IRAK-1) were measured by reverse transcriptase polymerase chain reaction and western blot respectively. Pretreatment of LPS significantly improved rat survival. Moreover, rats pretreated with LPS exhibited lower serum enzyme (ALT, AST and TBiL) level, lower production of inflammatory cytokines and more minor liver histopathological damage than rats without pretreatment of LPS. LPS pretreatment suppressed production of TLR4 and IRAK-1. LPS pretreatment also inhibited activation of hepatic NF-κB. These results indicated that endotoxin tolerance contributed to liver protection against D-GalN/LPS induced acute liver failure through down-regulation of TLR4 and NF-κB pathway.
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Sainan
S
Zhang
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Naibin
N
Yang
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Shunlan
S
Ni
Department of Infection Disease, Zhejiang Provincial Hospital of TCM Hangzhou, Zhejiang, P. R. China.
Wenyuan
W
Li
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Lanman
L
Xu
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Peihong
P
Dong
Department of Infection Disease, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, Zhejiang, P. R. China.
Mingqin
M
Lu
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005688:Galactosamine; D018836:Inflammation Mediators / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C498145:Rela protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D005688:Galactosamine; C547807:IRAK1 protein, rat; D053592:Interleukin-1 Receptor-Associated Kinases
D-GalN/LPS; Endotoxin tolerance; NF-κB; TLR4; liver failure