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

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

Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice

“…26 PDTC is another effective free radical scavenger. In vivo, PDTC protected mice from endotoxin and tumor necrosis factor a-induced lethal shock, 27,28 rabbits from staphylococcal enterotoxin A-induced fever 29 and cold perfusion-induced injury to orthotopic rat liver transplants. 30 In vitro, it has been reported to reduce the effect of ultraviolet radiation in experiments with cultured cell lines.…”

Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils

“…As a result, LPS stimulation results in rapid release of TNF-␣ and IL-1␤, whereas release of IL-10 is delayed (5). In the past, LPS-activated monocytes have been manipulated through the use of ␤-agonists (42), antioxidants (43), and adenosine receptor agonists (44,45), resulting in reduced production of proinflammatory cytokines and augmented IL-10 production. We have shown that contact with apoptotic neutrophils has a similar quantitative effect (Fig.…”

Regulation of Reticuloendothelial Iron Transporter MTP1 (Slc11a3) by Inflammation

“…6). Furthermore, administration of PDTC, a well characterized inhibitor of NF-B activation and TNF-␣ production (37), to mice prior to treatment with LPS did not alter the change in MTP1 expression induced by LPS (data not shown).…”