title: Ethyl pyruvate reduces liver injury at early phase but impairs regeneration at late phase in acetaminophen overdose.
abstract: BACKGROUND
  Inflammation may critically affect mechanisms of liver injury in acetaminophen (APAP) hepatotoxicity. Kupffer cells (KC) play important roles in inflammation, and KC depletion confers protection at early time points after APAP treatment but can lead to more severe injury at a later time point. It is possible that some inflammatory factors might contribute to liver damage at an early injurious phase but facilitate liver regeneration at a late time point. Therefore, we tested this hypothesis by using ethyl pyruvate (EP), an anti-inflammatory agent, to treat APAP overdose for 24-48 hours.
  
  
  METHODS
  C57BL/6 male mice were intraperitoneally injected with a single dose of APAP (350 mg/kg dissolved in 1 mL sterile saline). Following 2 hours of APAP challenge, the mice were given 0.5 mL EP (40 mg/kg) or saline treatment every 8 hours for a total of 24 or 48 hours.
  
  
  RESULTS
  Twenty-four hours after APAP challenge, compared to the saline-treated group, EP treatment significantly lowered serum transaminases (ALT/AST) and reduced liver injury seen in histopathology; however, at the 48-hour time point, compared to the saline therapy, EP therapy impaired hepatocyte regeneration and increased serum AST; this late detrimental effect was associated with reduced serum TNF-α concentration and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration.
  
  
  CONCLUSIONS
  Inflammation likely contributes to liver damage at an early injurious phase but improves hepatocyte regeneration at a late time point, and prolonged anti-inflammation therapy at a late phase is not beneficial.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA 15261, USA. bobyangr@yahoo.com
authors.forename: Runkuan
authors.initials: R
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zou
authors.forename: Marja-Leena
authors.initials: ML
authors.lastname: Koskinen
authors.forename: Jyrki
authors.initials: J
authors.lastname: Tenhunen
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063487:Prescription Drug Misuse; D011773:Pyruvates / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013997:Time Factors
chemical_list: D011773:Pyruvates; C046522:ethyl pyruvate; D000082:Acetaminophen