title: Pretreatment with lipopolysaccharide ameliorates Pseudomonas exotoxin A-induced hepatotoxicity in rats.
abstract: BACKGROUND
  Liver injury can be induced by various hepatotoxicants, including Pseudomonas aeruginosa exotoxin A (PEA). Our previous study indicated that PEA-induced rat hepatotoxicity was T cells and Kupffer cells dependent. Several reports have demonstrated that non-toxic doses of bacterial lipopolysaccharide (LPS) can protect liver against the chemicals-induced toxicity such as acetaminophen and concanavalin-A.
  
  
  OBJECTIVE
  This study aimed to investigate the protecting mechanisms of LPS on PEA-induced hepatotoxicity.
  
  
  RESULTS
  Rats pretreated with LPS (40 μg/kg, 12 h before PEA admission) significantly decreased animal mortality, serum enzyme (ALT, AST and T-bil) activities, histopathological changes and hepatocytes apoptosis following challenge with PEA. The concentrations of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were reduced, but IL-6 and IL-10 were increased in the serum. In addition, prior treatment of these LPS-pretreated rats with gadolinium chloride (GdCl3), a selective Kupffer cell depletion agent, markedly enhanced liver injury after PEA administration. In contrast, the pretreatment of LPS to T-cell deficient athymic nude rats still display significant attenuation of PEA-induced liver injury. This observation further confirmed our hypothesis that LPS ameliorate PEA-hepatotoxicity was through Kupffer cells but not T cells. Moreover, LPS-induced hepatoprotection ability was neutralized by co-treatment with anti-TNF-α antibodies, but not with anti-IFN-γ antibodies. Finally, replacement of LPS with RS-LPS (Rhodobacter sphaeroides LPS), a Toll like receptor-4 (TLR-4) antagonist, resulted in severe hepatotoxicity.
  
  
  CONCLUSIONS
  These results suggested that Kupffer cells, TNF-α and TLR-4 play central mediator roles during the hepatoprotection against PEA-induced hepatotoxicity conferred by LPS.
authors: Cheng-Hsin Veterinary Pathology Center, Taichung, Taiwan.
authors: Chien-Chao
authors: CC
authors: Chiu
authors: Yen-Te
authors: YT
authors: Huang
authors: Yu-Chih
authors: YC
authors: Wang
authors: Yi-Chih
authors: YC
authors: Chang
authors: Yung-Hao
authors: YH
authors: Ching
authors: Hans Hsien-Chuan
authors: HH
authors: Chen
authors: Hsiao-Li
authors: HL
authors: Chuang
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D004347:Drug Interactions; D005098:Exotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005682:Gadolinium / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D011549:Pseudomonas / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D001427:Bacterial Toxins; D005098:Exotoxins; D005682:Gadolinium; D007371:Interferon-gamma; D007378:Interleukins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C038958:gadolinium chloride