Pyrrolidine dithiocarbamate protects mice from lethal shock induced by LPS or TNF-alpha

Eur J Immunol. 1999 Jun;29(6):1890-900. doi: 10.1002/(SICI)1521-4141(199906)29:06<1890::AID-IMMU1890>3.0.CO;2-F.


Although important advances have been made in the development of antibiotics and medical intensive care technology in recent years, systemic response to infection remains a major health problem, with growing incidence and high mortality rates. Here we demonstrate the ability of the antioxidant agent pyrrolidine dithiocarbamate (PDTC) to inhibit the in vivo activation of NF-kappaB in lung and liver tissues, as well as the systemic release of TNF-alpha in lipopolysaccharide (LPS)-treated mice. The in vivo effect of PDTC on NF-kappaB activation in liver tissues involved the inhibition of both LPS-induced I kappaB-alpha degradation and the translocation of the p50 and p65 NF-kappaB subunits to the nucleus. In addition to protecting mice against lethal LPS doses, PDTC curtailed TNF-alpha-induced lethal shock. This effect was observed even after LPS injection, and when PDTC was administered at a time when TNF-alpha was already at maximum levels in serum. PDTC-treated mice survived despite high IL-1beta and IL-6 levels, induction of VCAM-1 and ICAM-1 expression or leukocyte infiltration in tissues known to be associated with LPS-induced shock, indicating that PDTC does not act by modifying these responses. Taken together, these results indicate that PDTC interferes with the production as well as the action of TNF-alpha, and points to a possible approach toward the treatment of septic shock.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / metabolism
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • I-kappa B Proteins*
  • Lipopolysaccharides / toxicity*
  • Liver / drug effects
  • Liver / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / therapeutic use
  • Shock, Septic / drug therapy
  • Shock, Septic / physiopathology
  • Shock, Septic / prevention & control*
  • Thiocarbamates / pharmacology*
  • Thiocarbamates / therapeutic use
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / toxicity*


  • Cell Adhesion Molecules
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Pyrrolidines
  • Thiocarbamates
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • pyrrolidine dithiocarbamic acid