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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Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. ⋯ We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
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Previous studies have shown that a decrease in protein kinase C (PKC) alpha levels contributes to hepatic failure and/or apoptosis during sepsis, and suppression of PKCalpha plays a critical role in triggering caspase-dependent apoptosis, which can modulate expression of Bcl-xL. However, the underlying molecular mechanism remains uncertain. In the present study, we examined whether a decrease in the nuclear PKCalpha levels causes hepatic apoptosis via modulation of cAMP-response element-binding protein (CREB) or nuclear factor-kappaB (NFkappaB), the crucial factors regulating the expression of prosurvival Bcl-xL. ⋯ Likewise, the binding activity of NFkappaB increased significantly, which was associated with a decrease in cytosolic inhibitory-kappaBalpha content. The in vitro suppression of PKCalpha also resulted in decreases in the phospho-CREB content and DNA-binding activity, which were accompanied by down-regulation of Bcl-xL and apoptosis, but no significant alteration in NFkappaB-binding activity. The in vivo and in vitro results suggest that the suppression of PKCalpha results in a decreased CREB phosphorylation and subsequent down-regulation of Bcl-xL, which may contribute to the hepatic apoptosis during sepsis.
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Acute normovolemic hemodilution (ANH) has been proposed to avoid the risks of allogenic transfusion. In reference to its cellular effects, ANH reports in the literature are scarce. Using electron microscopy (EM), we evaluated the effects of ANH on cardiac function and myocardial structure. ⋯ Electron microscopy analysis of the myocardium revealed slight lesions in cardiac cells in the HES group, and moderate-to-significant lesions in the LR group. In this animal species, ANH with HES resulted in better preservation of cardiac function, which was demonstrated by maintenance of systolic function and oxygenation parameters. Minor loss of cellular integrity with HES, in the presence of very low levels of hemoglobin, reinforces these findings.
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Randomized Controlled Trial Clinical Trial
Gentamicin improves hemodynamics in ovine septic shock after smoke inhalation injury.
Previously, our group developed an ovine model of hyperdynamic sepsis associated with acute lung injury. In this study, we sought to modify this sepsis model by the administration of gentamicin to more closely simulate the symptoms observed in human sepsis in the intensive care unit. In a prospective, controlled, randomized laboratory experiment, 18 female sheep were surgically prepared for chronic study. ⋯ In addition, the fluid requirement in the gentamicin group was significantly lower than in the control group. Pulmonary function remained stable in sham animals, but the PaO2/FiO2 ratio and shunt fraction deteriorated similarly in the control and the gentamicin groups. Because gentamicin improved hemodynamic variables and reduced the fluid requirement in this ovine model, we believe that this modified sepsis model might provide a clinically relevant and useful new approach for future studies focusing on hemodynamic variables and outcome.
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Most authorities believe that the greatest need for blood substitutes is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes, derived from hemoglobin. The hemoglobin-based oxygen carriers (HBOCs) tested currently in FDA Phase III clinical trials are polymerized hemoglobin solutions. ⋯ The potential efficacy of HBOCs extends beyond the temporary replacement for stored RBCs. Hemoglobin solutions might ultimately prove superior in delivering oxygen to ischemic or injured tissue. The current generation of HBOCs can be lifesaving for acute blood loss today, but the next generation might be biochemically tailored for specific clinical indications.