amanitins and Shock--Septic

The activation of the death receptors, tumor necrosis factor-receptor-1 (TNF-R1) or CD95, is a hallmark of inflammatory or viral liver disease. In different murine in vivo models, we found that livers depleted of gamma-glutamyl-cysteinyl-glycine (GSH) by endogenous enzymatic conjugation after phorone treatment were resistant against death receptor-elicited injury as assessed by transaminase release and histopathology. In apoptotic models initiated by engagement of CD95, or by injection of TNF or lipopolysaccharide into galactosamine-sensitized mice, hepatic caspase-3-like proteases were not activated in the GSH-depleted state. Under GSH depletion, also caspase-independent, TNF-R1-mediated injury (high-dose actinomycin D or alpha-amanitin), as well as necrotic hepatotoxicity (high-dose lipopolysaccharide) were entirely blocked. In the T-cell-dependent model of concanavalin A-induced hepatotoxicity, GSH depletion resulted in a suppression of interferon-gamma release, delay of systemic TNF release, hepatic nuclear factor-kappaB activation, and an abrogation of sinusoidal endothelial cell detachment as assessed by electron microscopy. When GSH depletion was initiated 3 hours after concanavalin A injection, ie, after the peak of early pro-inflammatory cytokines, livers were still protected. We conclude that sufficient hepatic GSH levels are a prerequisite for the execution of death receptor-mediated hepatocyte demise.

Topics: Amanitins; Animals; Antigens, CD; Apoptosis; Caspases; Cell Death; Concanavalin A; Cytokines; Dactinomycin; Dose-Response Relationship, Drug; Glutathione; Liver; Male; Mice; Mice, Inbred BALB C; Necrosis; Nucleic Acid Synthesis Inhibitors; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Shock, Septic

Group A streptococcal pyrogenic exotoxins (SPEs) A, B, and C and alpha-amanitin enhance host susceptibility to lethal endotoxin shock. The capacity of SPE C and alpha-amanitin to prepare rabbits for the enhancement phenomenon required pretreatment of the animals 1 to 2 h before giving endotoxin. Endotoxin clearance from the circulation of rabbits pretreated with either SPE C or alpha-amanitin was reduced. Even at the time of death, significant amounts of endotoxin remained in the circulation. It is proposed that the SPE and alpha-amanitin inhibit ribonucleic acid synthesis in Kupffer cells with concomitant alteration in reticuloendothelial clearnace function, allowing endotoxin to persist in the circulation and produce host injury. All three SPE types and alpha-amanitin inhibited ribonucleic acid synthesis by 50% or greater in whole liver cells. Kupffer cells, liver cell nuclei, and liver nuclear extracts; inhibition was observed liver cells from both mice and rabbits. The inhibitory effect by SPEs was dose dependent and was observed after as little as 15 min of preincubation with liver cells. The content of ribonucleic acid in liver nuclei of mice pretreated with either SPE C or alpha-amanitan was reduced, whereas total deoxyribonucleic acid and protein content remained unaltered.

Topics: Amanitins; Animals; Bacterial Toxins; Cell Nucleus; Dose-Response Relationship, Drug; Exotoxins; Female; Kupffer Cells; Liver; Male; Mice; Pyrogens; Rabbits; RNA; Shock, Septic; Streptococcus pyogenes