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

Although important advances have been made in the development of antibiotic s and medical intensive care technology in recent years, systemic response to infection remains a major health problem; with growing incidence and hig h mortality rates. Here we demonstrate the ability of the antioxidant agent pyrrolidine dithiocarbamate (PDTC) to inhibit the in vivo activation of NF -kappa B 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-kappa B activation in liver tissues involved the inhibition of both L PS-induced I kappa B-alpha degradation and the translocation of the p50 and p65 NF-kappa B subunits to the nucleus. In addition to protecting mice aga inst lethal LPS doses, PDTC curtailed TNF-alpha-induced lethal shock. This effect was observed even after LPS injection, and when PDTC was administere d at a time when TNF-alpha was already at maximum levels in serum. PDTC-tre ated mice survived despite high IL-1 beta and IL-6 levels, induction of VCA M-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 mod ifying these responses. Taken together, these results indicate that PDTC in terferes with the production as well as the action of TNF-alpha, and points to a possible approach toward the treatment of septic shock.