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 changes in protein expression by proteomic analysis in the sera of patients with sepsis and to identify new biomarkers of sepsis. A total of 45 consecutive patients with severe sepsis or septic shock (sepsis group), 22 healthy volunteers, and 23 patients undergoing off-pump coronary artery bypass grafting (control group). Serum samples from eight patients of each group underwent proteomic analysis involving removal of 12 major proteins and subsequent reversed-phase high-performance liquid chromatography fractionation and one-dimensional electrophoresis. ⋯ A positive correlation between sYKL-40 and blood IL-6 level on ICU admission was noted in the sepsis group (r = 0.465, P < 0.01). YKL-40 identified by proteomic analysis is considered as a biomarker of sepsis. However, further investigation is needed to clarify its roles and clinical usefulness as a biomarker.
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Liver dysfunction affects a variety of metabolic pathways in the critically ill, but mechanisms remain poorly understood. We prospectively assessed markers of hepatic injury and function in sepsis and I/R injury in vivo and molecular mechanisms in human liver tissue ex vivo. Markers of hepatocellular injury, synthesis, and excretion, including plasma disappearance rate of indocyanine green (ICG), were measured in 48 patients with severe sepsis. ⋯ In conclusion, standard liver tests lack the required sensitivity to assess hepatic injury and function in the critically ill. Dye excretion better reflects excretory and/or microvascular dysfunction but still underestimates impaired canalicular transport. The observed differential susceptibility of the polar surfaces of human hepatocytes has potential implications for monitoring liver function and drug-induced liver injury.
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Sialic-acid-binding immunoglobulin-like lectin (Siglec) 9 mediates death signals in neutrophils. The objective of this study was to determine the heterogeneity of neutrophil death responses in septic shock patients and to analyze whether these ex vivo data are related to the severity and outcome of septic shock. In this prospective cohort study, blood samples of patients with septic shock (n = 26) in a medical-surgical intensive care unit (ICU) were taken within 24 h of starting the treatment of septic shock (phase A), after circulatory stabilization (phase B), and 10 days after admission or at ICU discharge if earlier (phase C). ⋯ Taken together, septic shock patients exhibit different ex vivo death responses of blood neutrophils after Siglec-9 ligation early in shock. Both the resistance and the increased susceptibility to Siglec-9-mediated neutrophil death tend to normalize within 72 h after shock. Further studies are required to understand the role of Siglec-9-mediated neutrophil death in septic shock.
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The purpose of the present study was to test the hypothesis that endogenous NO negatively affects translation in skeletal muscle cells after exposure to a combination of endotoxin (LPS) and interferon-gamma (IFN-gamma). Individually, LPS and IFN-gamma did not alter protein synthesis, but in combination, they inhibited protein synthesis by 80% in C2C12 myotubes. The combination of LPS and IFN-gamma dramatically downregulated the autophosphorylation of the mammalian target of rapamycin and its substrates S6K1 and 4EBP-1. ⋯ LPS/IFN-gamma downregulated the phosphorylation of multiple Akt substrates, including the proline-rich Akt substrate 40, while enhancing the phosphorylation of raptor on a 5'-AMP-activated kinase (AMPK)-regulated site. The negative effects of LPS/IFN-gamma were blunted by the AMPK inhibitor compound C. The data suggest that, in combination, LPS and IFN-gamma induce a prolonged expression of NOS2 and excessive production of NO that reciprocally alter Akt and AMPK activity and consequently downregulate translation via reduced mammalian target of rapamycin signaling.
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The vasoconstrictive and proinflammatory peptide endothelin 1 (ET-1) is highly involved in the pathogenesis of sepsis and associated lung injury. Systemic administration of ET-receptor antagonists has been beneficial in experimental pulmonary hypertension. We wanted to study the effects of inhaled tezosentan, a dual endothelin-receptor antagonist on endotoxin-induced pulmonary hypertension, deterioration of gas exchange, and edema formation. ⋯ Despite similar effects on pulmonary hypertension systemic treatment resulted in significantly higher plasma levels of ET-1 (twofold) and tezosentan (10- to 100-fold). Inhalation of the dual ET-receptor antagonist tezosentan was feasible and efficiently counteracted endotoxin-induced pulmonary hypertension. These effects were obtained with only minor systemic uptake of tezosentan and without affecting circulating levels of plasma ET-1 as compared with intravenous administration.