Ethyl pyruvate protects rats from phosgene-induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression

J Appl Toxicol. 2013 Jan;33(1):71-7. doi: 10.1002/jat.1713. Epub 2011 Aug 5.


Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 µm) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2).

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cell Line
  • Chemical Warfare Agents / toxicity
  • Cyclooxygenase 2 / metabolism
  • Lung / drug effects*
  • Lung / pathology
  • Macrophages / drug effects
  • Macrophages / pathology
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide / analysis
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Organ Size / drug effects
  • Phosgene / toxicity*
  • Protective Agents / pharmacology*
  • Pulmonary Edema / chemically induced
  • Pulmonary Edema / pathology
  • Pulmonary Edema / prevention & control*
  • Pyruvates / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Chemical Warfare Agents
  • Protective Agents
  • Pyruvates
  • ethyl pyruvate
  • Phosgene
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinases