title: Dithiocarbamates ameliorate the effects of endotoxin in a rabbit model of disseminated intravascular coagulation.
abstract: Induction of tissue factor (TF) activity by endotoxin and cytokines is an important mechanism for initiation of disseminated intravascular coagulation (DIC) seen in patients with gram-negative sepsis. Based on data from an in vitro study in which dithiocarbamates abrogated endothelial cell TF activity by inhibition of the NF-kappaB pathway, we investigated whether dithiocarbamates had in vivo activity in an animal model of DIC. Dithiocarbamates ameliorated the adverse clinical and histological effects of endotoxin-induced DIC, including morbidity, hypofibrinogenemia, and target organ damage, especially in the liver and kidney, even when given up to 1 hour after administration of endotoxin. This pilot study confirms the key role of the nuclear factor-kappa beta (NF-kappaB) pathway in induction of TF activity in initiating sepsis-associated DIC and suggests that dithiocarbamates may be useful in treatment of DIC associated with excessive TF expression because of gram-negative sepsis. Additional studies of dithiocarbamates in DIC models are warranted.
authors.affiliation: Department of Medicine, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Drollinger
authors.forename: J C
authors.initials: JC
authors.lastname: Netser
authors.forename: G M
authors.initials: GM
authors.lastname: Rodgers
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D011817:Rabbits; D013859:Thiocarbamates / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D004731:Endotoxins; D016328:NF-kappa B; D013859:Thiocarbamates; D005340:Fibrinogen; D013925:Thromboplastin