170 research outputs found

    Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis

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    INTRODUCTION: Sepsis involves overwhelming inflammatory responses with subsequent immune-suppression that can lead to multiple organ dysfunction and ultimately death. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory protein found to have multiple biological activities against autoimmune and inflammatory diseases. MFG-E8 contains an Arg-Gly-Asp (RGD) motif involved in cell-cell and cell-matrix interactions. In sepsis, excessive neutrophils migration through endothelial cells and matrix to sites of inflammation results in organ damage. We hypothesized that MFG-E8-derived short peptides (MSP) flanking its RGD motif could provide protection against organ injury in sepsis. METHODS: The differentiated human neutrophil-like HL-60 cells (dHL60) were incubated with a series of peptides flanking the RGD motif of human MFG-E8 for a cell adhesion assay to fibronectin or human pulmonary artery endothelial cells (PAECs). For the induction of sepsis, male C57BL/6 mice (20–25 g) were subjected to cecal ligation and puncture (CLP). Peptide MSP68 (1 mg/kg body weight) or normal saline (vehicle) was injected intravenously at 2 h after CLP. Blood and tissue samples were collected at 20 h after CLP for various measurements. RESULTS: After screening, peptide MSP68 (VRGDV) had the highest inhibition of dHL-60 cell adhesion to fibronectin by 55.8 % and to PAEC by 67.7 %. MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-α by 61.9 % and 22.1 %, respectively after CLP. MSP68 improved the integrity of microscopic architectures, decreased IL-6 levels in the lungs by 85.1 %, and reduced apoptosis. MSP68 treatment also significantly reduced the total number of neutrophil infiltration by 61.9 % and 48.3 % as well as MPO activity by 40.8 % and 47.3 % in the lungs and liver, respectively, after CLP. Moreover, the number of bacteria translocated to mesenteric lymph nodes was decreased by 57 % with MSP68 treatment. Finally, the 10-day survival rate was increased from 26 % in the vehicle group to 58 % in the MSP68-treated group. CONCLUSIONS: MSP68 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice. Thus, MSP68 may be a potential therapeutic agent for treating sepsis

    High-resolution ultraviolet spectroscopy of PG1159-035 with HST and FUSE

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    PG1159-035 is the prototype of the PG1159 spectral class which consists of extremely hot hydrogen-deficient (pre-) white dwarfs. It is also the prototype of the GW Vir variables, which are non-radial g-mode pulsators. The study of PG1159 stars reveals insight into stellar evolution and nucleosynthesis during AGB and post-AGB phases. We perform a quantitative spectral analysis of PG1159-035 focusing on the abundance determination of trace elements. We have taken high-resolution ultraviolet spectra of PG1159-035 with the Hubble Space Telescope and the Far Ultraviolet Spectroscopic Explorer. They are analysed with non-LTE line blanketed model atmospheres. We confirm the high effective temperature with high precision (Teff=140,000+/-5000 K) and the surface gravity of logg=7. For the first time we assess the abundances of silicon, phosphorus, sulfur, and iron. Silicon is about solar. For phosphorus we find an upper limit of solar abundance. A surprisingly strong depletion of sulfur (2% solar) is discovered. Iron is not detected, suggesting an upper limit of 30% solar. This coincides with the Fe deficiency found in other PG1159 stars. We redetermine the nitrogen abundance and find it to be lower by one dex compared to previous analyses. The sulfur depletion is in contradiction with current models of AGB star intershell nucleosynthesis. The iron deficiency confirms similar results for other PG1159 stars and is explained by the conversion of iron into heavier elements by n-capture in the s-processing environment of the precursor AGB star. However, the extent of the iron depletion is stronger than predicted by evolutionary models. The relatively low nitrogen abundance compared to other pulsating PG1159 stars weakens the role of nitrogen as a distinctive feature of pulsators and non-pulsators in the GW Vir instability strip.Comment: A&A accepted, 13 pages, 10 figure

    Vasopressors and Inotropes in the Treatment of Human Septic Shock: Effect on Innate Immunity?

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    Catecholamines have been suggested to modulate innate immune responses in experimental settings. The significance hereof in the treatment of human septic shock is unknown. We therefore sought if and how vasopressor/inotropic doses relate to pro-inflammatory mediators during treatment of septic shock. We prospectively studied 20 consecutive septic shock patients. For 3 days after admission, hemodynamic variables, lactate and plasma levels of interleukins (IL)-6 and 8, tumor necrosis factor (TNF)-α, and elastase-α1-antitrypsin were measured six hourly. Doses of vasoactive drugs were recorded. Of the 20 patients, nine died in the intensive care unit. Dobutamine doses were positively associated and related to TNF-α plasma levels, independently of disease severity, hemodynamics, and outcome, in multivariable models. Dopamine doses were positively associated with IL-6, and norepinephrine was inversely associated with IL-8 and TNF-α levels. Our observations suggest that catecholamines used in the treatment of human septic shock differ in their potential modulation of the innate immune response to sepsis in vivo. Dobutamine treatment may contribute to circulating TNF-α and dopamine to IL-6, independently of activated neutrophils. Conversely, norepinephrine may lack pro-inflammatory actions
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