Ethyl pyruvate reduces acute lung injury via regulation of iNOS and HO-1 expression in endotoxemic rats

J Surg Res. 2011 May 15;167(2):e323-31. doi: 10.1016/j.jss.2011.01.006. Epub 2011 Feb 2.


Background: Ethyl pyruvate (EP) has been shown to attenuate lipopolysaccharide (LPS)-induced acute lung injury (ALI). Induction of heme oxygenase-1 (HO-1) and suppression of inducible nitric oxide synthase (iNOS) expression provide cytoprotection in lung and vascular injury. The aim of this study is to evaluate whether the beneficial effect of EP on lung inflammation is related to HO-1 induction in a rat model of LPS-induced ALI.

Materials and methods: Rats were administered LPS (30 mg/kg) by intravenous infusion for 4 h to induce ALI. EP (20, 40, and 60 mg/kg/4 h i.v. infusion) or vehicle was given 1 h after LPS initiation.

Results: EP 40 and 60 mg/kg attenuated plasma levels of TNF-α and IL-6 caused by LPS, and further increased IL-10 levels compared with the LPS group. At 6 h after LPS initiation, iNOS protein expression in lungs and plasma NO metabolite levels were markedly increased, which were reduced by EP 60 mg/kg. LPS caused a significant HO-1 induction, whereas administration of EP 60 mg/kg significantly induced higher HO-1 expression compared with the LPS group. The beneficial effects of EP on cytokines and iNOS expression were reversed by HO-1 inhibitor SnPP. EP significantly suppressed phosphorylated p38 MAPK and increased phosphorylated ERK1/2 protein levels in the lung tissue. The edema and infiltration of neutrophils into lungs was reduced by EP.

Conclusion: EP reduced LPS-induced ALI, which may be mediated by induction of HO-1. The underlying mechanisms are associated with suppression of p38 MAPK and increase of ERK1/2 signaling pathway activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / metabolism*
  • Acute Lung Injury / prevention & control*
  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endotoxemia / metabolism*
  • Endotoxemia / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / metabolism*
  • Interleukin-6 / blood
  • Lipopolysaccharides / adverse effects
  • Male
  • Metalloporphyrins / pharmacology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nitric Oxide Synthase Type II / metabolism*
  • Protoporphyrins / pharmacology
  • Pyruvates / therapeutic use*
  • Rats
  • Rats, Wistar
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / blood


  • Enzyme Inhibitors
  • Interleukin-6
  • Lipopolysaccharides
  • Metalloporphyrins
  • Protoporphyrins
  • Pyruvates
  • Tumor Necrosis Factor-alpha
  • ethyl pyruvate
  • tin protoporphyrin IX
  • Nitric Oxide Synthase Type II
  • Heme Oxygenase-1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases