Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced thymocyte apoptosis.
Sepsis induces extensive lymphocyte cell death that may contribute to immune depression and morbidity/mortality in the disorder. bcl-2 is a member of a new class of oncogenes that prevents cell death from an array of noxious stimuli. Transgenic mice that overexpress BCL-2 in T lymphocytes are resistant to sepsis-induced T cell apoptosis, and mortality was decreased in sepsis. The purpose of this study was to identify key initiator and executioner "caspases" involved in sepsis-induced lymphocyte apoptosis and to determine if BCL-2 acts prior to caspase activation. ⋯ BCL-2 prevented sepsis-induced thymocyte apoptosis and inhibited activation of all caspases. We conclude that sepsis causes activation of multiple caspases and that BCL-2 acts upstream as an inhibitor of caspase activation. The pattern of caspase activation suggests a mitochondrial mediated pathway.
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Polymicrobial sepsis is characterized by an early, hyperdynamic phase (i.e., 2-10 h after cecal ligation and puncture [CLP]) followed by a late, hypodynamic phase (16 h after CLP or later). Although nitric oxide (NO) plays an important role in the pathophysiologic response during sepsis, it remains unknown how early NO is upregulated after the onset of sepsis and which organs are responsible for producing the increased amount of NO. To study this, male rats were subjected to sepsis by CLP followed by fluid resuscitation. ⋯ Similarly, iNOS gene expression was upregulated in the kidneys, small intestines, and liver. Thus, the above organs appear to be important sites responsible for producing the increased NO during sepsis. Because we previously showed that the hyperdynamic response occurs as early as 2 h after CLP and because iNOS-derived NO production is not upregulated earlier than 10 h after the onset of Sepsis, it appears that factors other than NO are responsible for producing the hyperdynamic response during sepsis.
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In our study the pathomechanism of sepsis-induced early myocardial depression was investigated. We determined the effects of the inducible nitric oxide synthase inhibitor and free radical scavenger mercaptoethylguanidine (MEG) on the myocardial contractility, the endothelial and inducible nitric oxide synthase (eNOS and iNOS) activities, and the activation and tissue accumulation of polymorphonuclear leukocytes in hyperdynamic endotoxemia in dogs. Group 1 served as endotoxemic control. ⋯ The compound dose-dependently decreased the in vitro activation of previously resting granulocytes. Our study demonstrates that iNOS do not contribute to the early cardiac failure in endotoxemia. MEG selectively inhibits iNOS in vivo, but its beneficial effects are rather related to the decreases in leukocyte and free radical-mediated myocardial dysfunction during early endotoxemia.