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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To investigate the molecular mechanism underlying heme oxygenase-1 (HO-1)-modulated infiltration of neutrophils, the sepsis model of cecal ligation and puncture in Sprague-Dawley rats was used. In vivo induction and suppression of HO-1 were performed by pretreatment with cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX, respectively. Tricarbonyldichlororuthenium(II) dimer, [Ru(CO)₃Cl₂]₂ (a carbon monoxide [CO] releaser), and hemoglobin (a CO scavenger) were used to examine the participation of HO-1/CO in the effect of CoPP pretreatment on formylated peptide (fMLP)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. ⋯ Moreover, anisomycin diminished the suppressive effects of CoPP pretreatment on fMLP-induced migration, actin polymerization, polarization, and migration speed of neutrophils. These results suggest that HO-1 in neutrophil attenuates its infiltration during sepsis via the inactivation of p38 MAPK. Understanding the mechanism that diminishes neutrophil infiltration by HO-1 may help prevent hepatic failure during sepsis.
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A small-volume therapeutic approach based on the biochemistry of hibernating mammals was evaluated to test the hypothesis that passive hypothermia and systemic administration of d-β-hydroxybutyrate (d-BHB) plus melatonin will increase survival of animals subjected to hemorrhagic shock ([HS] 60% blood loss). Anesthetized Sprague-Dawley male rats (320 ± 23 g) underwent controlled loss of 60% blood volume. Rats were instrumented to measure mean arterial pressure, body temperature (Tb), and heart rate. ⋯ In experiments where the shed blood was returned after 1 h of 60% blood loss, 4% fluid replacement with 4 M d-BHB plus 43 mM melatonin significantly prolonged survival up to 10 days after blood return compared with 4 M NaCl plus 43 mM melatonin and other control solutions (n = 10). We conclude that a slow decrease in animal Tb resulting from 60% blood loss, combined with infusion of 4 M d-BHB plus 43 mM melatonin, was beneficial for long-term survival after return of shed blood. This HS therapy is designed as a portable low-volume solution for further evaluation in a large-animal model and is ultimately intended for use in HS patients by first responders.
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Clinical Trial
Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock.
In this study, we examined the effects of direct hemoperfusion through filters with immobilized polymyxin B (PMX-DHP) on leukocyte function and plasma levels of cytokines in patients with septic shock. We found that PMX-DHP caused increased expression of C-X-C chemokine receptor 1 (CXCR1) and CXCR2, along with decreased expression of CD64 and CD11b, by circulating neutrophils in patients with septic shock. Plasma levels of cytokines, including interleukin 6 (IL-6), IL-8, IL-10, and high-mobility group box 1, were elevated in patients with septic shock compared with healthy controls, but cytokine levels were not altered by PMX-DHP. ⋯ Neutrophils isolated from the blood after ex vivo PMX perfusion caused less damage to an endothelial cell monolayer than cells from sham-treated blood, whereas neutrophil phagocytosis of opsonized Escherichia coli was unaffected. These results indicate that PMX-DHP selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage. Selective removal of activated neutrophils using PMX-DHP may improve the systemic inflammatory response in patients with septic shock.
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Comparative Study
Peritoneal negative pressure therapy prevents multiple organ injury in a chronic porcine sepsis and ischemia/reperfusion model.
Sepsis and hemorrhage can result in injury to multiple organs and is associated with an extremely high rate of mortality. We hypothesized that peritoneal negative pressure therapy (NPT) would reduce systemic inflammation and organ damage. Pigs (n = 12) were anesthetized and surgically instrumented for hemodynamic monitoring. ⋯ Our data suggest NPT efficacy is partially due to an attenuation of peritoneal inflammation by the removal of ascites. However, the exact mechanism needs further elucidation. The clinical implication of this study is that sepsis/trauma can result in an inflammatory ascites that may perpetuate organ injury; removal of the ascites can break the cycle and reduce organ damage.