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
-
We studied the effects of a novel pterin antagonist of NO synthase, the 4-amino analogue of tetrahydrobiopterin (4-ABH4), in a rat model of endotoxic shock and compared its properties with those of N(G)-monomethyl L-arginine (L-NMMA). Treatment with a bolus dose of 4-ABH4 at 2 h after LPS challenge significantly improved the 6-day survival rate, compared with the controls treated with saline. L-NMMA treatment did not significantly influence the survival rate. ⋯ Treatment of RAW264.7 murine macrophages with 4-ABH4 but not with L-NMMA suppressed endotoxin-induced tumor necrosis factor-alpha release by the cells, whereas nitrite in the supernatant decreased in a dose-dependent fashion in both assay systems. Our data show that 4-ABH4, an inhibitor of inducible NO synthase, significantly improves survival in a rat model of endotoxic shock when administered in a bolus dose that does not reduce plasma total nitrite + nitrate levels. Because we observed no overt signs of toxicity and no influence on organ-specific tetrahydrobiopterin levels, we conclude that the novel compound 4-ABH4 is a promising drug candidate for protection against endotoxin-related mortality.
-
The aim of the present study was to evaluate the effects of hyperbaric oxygen (HBO) therapy on multiple organ failure induced by zymosan. Administration of zymosan (500 mg/kg) in the rat induced neutrophil infiltration in the lung, liver, and intestine as evaluated by increase in myeloperoxidase (MPO) activity. Therefore, lipid peroxidation was significantly increased in zymosan-treated rats. ⋯ HBO (2 absolute Atmosphere) exposure attenuates the increase in the tissue levels of MPO and malondialdehyde (MDA) caused by zymosan in the lung, liver, and intestine. In addition, HBO (2 absolute Atmosphere) was effective in preventing the development of lung, liver, and intestine injury. Taken together, the present results demonstrate that HBO may also be an efficacious treatment in multiple organ failure induced by zymosan.
-
Using a standardized moderate splenic injury (MSI) model of uncontrolled hemorrhagic shock, we studied the effect of vigorous crystalloid or colloid fluid resuscitation on the hemodynamic response and survival time in rats. The animals were randomized into 6 groups: group 1 (n = 8) sham-operated, group 2 (n = 10) MSI untreated, group 3 (n = 10) MSI treated with 41.5 mL/kg Ringer's lactate (large-volume Ringer's lactate [LVRL]), group 4 (n = 10) MSI treated with 5 mL/kg 7.5% NaCl (hypertonic saline [HTS]), group 5 (n = 10) MSI treated with 7.5 mL/kg hydroxyethyl starch (HES-7.5), group 6 (n = 10) MSI treated with 15 mL/kg hydroxyethyl starch (HES-15). After MSI, mean arterial pressure (MAP) in group 2 decreased from 105.0+/-5.6 to 64.0+/-12.7 mmHg (P < 0.001) after 60 min. ⋯ HES-15 infusion resulted in an increase in blood loss to 48.2+/-7.3% (P < 0.05), and mean survival time of 133.0+/-27.7 min. Large-volume Ringer's lactate (LVRL) or hydroxyethyl starch (HES-15) infusion in uncontrolled hemorrhagic shock after moderate splenic injury resulted in a significant increase in intra-abdominal bleeding, but survival time remained unchanged compared with untreated, small-volume HTS-, or HES-7.5-treated animals. The hemodynamic response to large-volume crystalloid or colloid infusion was similar to moderate large-vessel injury.
-
Hyperdynamic shock can be modeled in pigs by chronic administration of a continuous, low-dose infusion of endotoxin. Lipopolysaccharide (LPS, E. coli 0111:B4, 80 ng/kg/min i.v.) initially resulted in a hypodynamic shock state with significant decreases in mean arterial pressure (112+/-3 mmHg at baseline to 94+/-4 mmHg at 8 h) and cardiac index (5.35+/-0.32 L/min/m2 at baseline to 4.07+/-0.32 L/min/m2 at 4 h). Eight hours after the initiation of the LPS infusion, cardiac index rose to above baseline values (5.82+/-0.4 L/min/m2 at 8 h) and remained elevated for the duration of the 48-h study (6.54+/-0.39 L/min/m2 at 48 h). ⋯ Serum concentrations of tumor necrosis factor were increased after 2 h of LPS infusion, but did not remain elevated above baseline concentrations for more than about 4 h despite continuous LPS challenge. Concentrations of tumor necrosis factor did not differ between arterial and portal venous samples. This model of hyperdynamic shock should be useful to assess potential therapies for septic shock.
-
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.