title: Ethyl pyruvate protects against experimental acute-on-chronic liver failure in rats.
abstract: OBJECTIVE
  To investigate the protective effects of ethyl pyruvate (EP) on acute-on-chronic liver failure (ACLF) in rats.
  
  
  METHODS
  An ACLF model was established in rats, and animals were randomly divided into normal, model and EP treatment groups. The rats in EP treatment group received EP (40 mg/kg) at 3 h, 6 h, 12 h and 24 h after induction of ACLF. Serum endotoxin, high mobility group box-1 (HMGB1), alanine transaminase (ALT), tumor necrosis factor-α (TNF-α), interferon-α (IFN-γ), interleukin (IL)-10 and IL-18 levels, changes of liver histology and HMGB1 expressions in liver tissues were detected at 48 h after induction of ACLF. The effects of EP on the survival of ACLF rats were also observed.
  
  
  RESULTS
  Serum levels of endotoxin (0.394 ± 0.066 EU/mL vs 0.086 ± 0.017 EU/mL, P < 0.001), HMGB1 (35.42 ± 10.86 μg/L vs 2.14 ± 0.27 μg/L, P < 0.001), ALT (8415.87 ± 3567.54 IU/L vs 38.64 ± 8.82 IU/L, P < 0.001), TNF-α (190.77 ± 12.34 ng/L vs 124.40 ± 4.12 ng/L, P < 0.001), IFN-γ (715.38 ± 86.03 ng/L vs 398.66 ± 32.91 ng/L, P < 0.001), IL-10 (6.85 ± 0.64 ng/L vs 3.49 ± 0.24 ng/L, P < 0.001) and IL-18 (85.19 ± 3.49 ng/L vs 55.38 ± 1.25 ng/L, P < 0.001) were significantly increased, and liver tissues presented severe pathological injury in the model group compared with the normal group. However, EP administration significantly improved hepatic histopathology and reduced the serum levels of endotoxin (0.155 ± 0.045 EU/mL vs 0.394 ± 0.066 EU/mL, P < 0.001) and inflammatory cytokines (11.13 ± 2.58 μg/L vs 35.42 ± 10.86 μg/L for HMGB1, 3512.86 ± 972.67 IU/L vs 8415.87 ± 3567.54 IU/L for ALT, 128.55 ± 5.76 ng/L vs 190.77 ± 12.34 ng/L for TNF-α, 438.16 ± 38.10 ng/L vs 715.38 ± 86.03 ng/L for IFN-γ, 3.55 ± 0.36 ng/L vs 6.85 ± 0.64 ng/L for IL-10, and 60.35 ± 1.63 ng/L vs 85.19 ± 3.49 ng/L for IL-18, respectively, P < 0.001), and the levels of HMGB1 in liver tissues regardless of treatment time after induction of ACLF. EP treatment at the four time points prolonged the median survival time of ACLF rats (60 h) to 162 h, 120 h, 102 h and 78 h, respectively (χ(2) = 41.17, P < 0.0001).
  
  
  CONCLUSIONS
  EP administration can protect against ACLF in rats, and is a potential and novel therapeutic agent for severe liver injury.
authors.affiliation: Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
authors.forename: Lu-Wen
authors.initials: LW
authors.lastname: Wang
authors.forename: Li-Kun
authors.initials: LK
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Can-Ming
authors.initials: CM
authors.lastname: He
authors.forename: Zuo-Jiong
authors.initials: ZJ
authors.lastname: Gong
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D019610:Cytoprotection; D004195:Disease Models, Animal; D058625:End Stage Liver Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004731:Endotoxins / Q000097:blood; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004731:Endotoxins; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D020011:Protective Agents; D011773:Pyruvates; C046522:ethyl pyruvate