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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Clinical Trial Controlled Clinical Trial
NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
Activation of the nuclear regulatory factor NF-kappaB occurs in the lungs of patients with the acute respiratory distress syndrome (ARDS) and may contribute to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in this setting. Because of the important role that NF-kappaB activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kapppaB counterregulatory mechanisms, involving IkappaB proteins, in alveolar macrophages obtained from 7 control patients without lung injury and 11 patients with established ARDS. Cytoplasmic levels of the NF-kappaB subunits p50, p65, and c-Rel were significantly decreased in alveolar macrophages from patients with ARDS, consistent with enhanced migration of liberated NF-kappaB dimers from the cytoplasm to the nucleus. ⋯ In this setting, appropriate counterregulatory mechanisms to normalize nuclear levels of NF-kappaB and to suppress NF-kappaB-mediated transcription, such as increased cytoplasmic and nuclear IkappaBalpha levels or decreased Bcl-3 levels, appeared to be induced. Nevertheless, even though counterregulatory mechanisms to NF-kappaB activation are activated in lung macrophages of patients with ARDS, NF-kappaB remains activated. These results suggest that fundamental abnormalities in transcriptional mechanisms involving NF-kappaB and important in the inflammatory response occur in the lungs of patients with ARDS.
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Comparative Study
Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture.
Sepsis remains a serious clinical problem despite intense efforts to improve survival. Experimental animal models of sepsis have responded dramatically to immunotherapy blocking the activity of cytokines. Despite these preclinical successes, human clinical trials have not demonstrated any improvement in survival. ⋯ In contrast, cytokine levels in the CLP model were continuing to increase at the 8 h-time point and often exceeded the LPS-induced values at this time. Our data demonstrate that the LPS and CLP models have similar mortality but significant differences in the kinetics and magnitude of cytokine production. Immunotherapy for sepsis based on cytokine production after LPS challenge is misdirected because the LPS model does not accurately reproduce the cytokine profile of sepsis.
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Leukocyte-endothelial cell interactions play an important role in mediating organ dysfunctions observed after hemorrhagic shock. P-selectin is the first endothelial cell adhesion molecule to be upregulated after an ischemic insult. The objective of this study was to define kinetics of P-selectin expression in different regional vascular beds of mice exposed to hemorrhagic shock. ⋯ While hemorrhagic shock of 40 mmHg did not cause P-selectin upregulation in kidneys, hemorrhage to 30 mmHg did elicit a significant increase at 5 h after resuscitation (P < 0.001). We conclude that P-selectin is upregulated after resuscitation of hemorrhagic shock in lungs, liver, heart, stomach, and intestines. P-selectin upregulation in kidneys only takes place after more severe hemorrhagic shock.
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Expression of the inducible isoform of nitric oxide (NO) synthase, and the formation of peroxynitrite from NO and superoxide are responsible for some of the pathophysiological alterations seen during reperfusion injury and in various inflammatory conditions. Some of the effects of peroxynitrite are related to DNA single-strand breakage, and activation of poly (ADP-ribose) synthetase. Here we investigated the effect of nicaraven (2(R,S)-1,2-bis(nicotinamido)propane), a known hydroxyl radical scavenger compound and neuroprotective agent, on several NO- and peroxynitrite related pathways in vitro, and in shock and inflammation in vivo. ⋯ Nicaraven (at 10-100 microg/paw) exerted significant protective effects in the carrageenan-induced paw edema model and (at 100 mg/kg i.v.) reduced neutrophil infiltration and histological damage in splanchnic artery occlusion-reperfusion injury. However, nicaraven failed to alter the course of hemorrhagic and endotoxic shock and arthritis in rodent models. The current data indicate the limited role of hydroxyl radicals in the pathogenesis of the inflammatory conditions tested.
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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.