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

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Abstract
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‐κB in lung and liver tissues, as well as the systemic release of TNF‐α in lipopolysaccharide (LPS)‐treated mice. The in vivo effect of PDTC on NF‐κB activation in liver tissues involved the inhibition of both LPS‐induced IκB‐α degradation and the translocation of the p50 and p65 NF‐κB subunits to the nucleus. In addition to protecting mice against lethal LPS doses, PDTC curtailed TNF‐α‐induced lethal shock. This effect was observed even after LPS injection, and when PDTC was administered at a time when TNF‐α was already at maximum levels in serum. PDTC‐treated mice survived despite high IL‐1β 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‐α, and points to a possible approach toward the treatment of septic shock.