Pyrrolidine dithiocarbamate protects mice from lethal shock induced by LPS or TNF-alpha.
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.
Lauzurica
P
P
Servicio de Immunología, Hospital de la Princesa, Madrid, Spain.
Martínez-Martínez
S
S
Marazuela
M
M
Gómez del Arco
P
P
Martínez
C
C
Sánchez-Madrid
F
F
Redondo
J M
JM
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D013859:Thiocarbamates / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000633:toxicity*
D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid