Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction

Endotoxemia; Inflammation; Mitochondrial functionEndotoxemia; Inflamación; Función mitocondrialEndotoxèmia; Inflamació; Funció mitocondrialBackground and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.Open access funding provided by Lund University. This study was supported by grants from the Marianne and Marcus Wallenberg Foundation the Swedish Heart and Lung Foundation, the Swedish Research Council, the Bundy Academy foundation at Lund University, Skåne Region Research Funds, Malmö University Hospital Funds, the Crafoord Foundation, the Royal Physiographic Society in Lund, Swedish Research Council, Östergotland Region Research Funds, and the Ministry of Research and Education of Romania (PNRR-C9/I8-CF148)

Growth and characterization of chromium carbide films deposited by high rate reactive magnetron sputtering for electrical contact applications

Chromium carbide films with different phase contents were deposited at 126±26 °C by industrial high rate reactivemagnetron sputtering, using both direct current magnetron sputtering (DCMS) and high power impulsemagnetron sputtering (HiPIMS). Film structure and properties were studied by SEM, XRD, TEM, XPS, NRA, Raman spectroscopy, nanoindentation, unlubricated reciprocating sliding experiments, and a laboratory setup to measure electrical contact resistance. The films consisted of amorphous a-CrCy, a nanocrystalline minority phase of metastable cubic nc-CrCx, and a hydrogenated graphite-like amorphous carbon matrix (a-C:H). The DCMS and HiPIMS processes yielded films with similar phase contents and microstructures, as well as similar functional properties. Low elastic modulus, down to 66 GPa, indicated good wear properties via a hardness/elastic modulus (H/E) ratio of 0.087. Unlubricated steady-state friction coefficients down to 0.13 were obtained for films with 69 at.% carbon, while the electrical contact resistance could be reduced by two orders of magnitude by addition of a-C:H phase to purely carbidic films. The present films are promising candidates for sliding electrical contact applications

Influence of ionization degree on film properties when using high power impulse magnetron sputtering

Chromium thin films are deposited by combining direct current magnetron sputtering and high power impulse magnetron sputtering (HiPIMS) on a single cathode in an industrial deposition system. While maintaining a constant deposition rate and unchanged metal ion energy distribution function, the fraction of the total power supplied by either deposition technique is altered, and thereby also the metal ion to metal neutral ratio of the deposition flux. It is observed that the required total average power needed to be proportionally increased as the HiPIMS fraction is increased to be able to keep a constant deposition rate. The influence on microstructure, electrical, and electrochemical properties of the films is investigated and shows improvements with the use of HiPIMS. However, considerable influence of the studied properties occurs already when only some 40% of the total power is supplied by the HiPIMS technique. Further increase of the HiPIMS power fraction results in comparatively minor influence of the studied properties yet significant deposition rate efficiency reduction. The results show that the degree of ionization can be controlled separately, and that the advantages associated with using HiPIMS can be obtained while much of the deposition rate reduction, often reported for HiPIMS, can be avoided.Funding Agencies|Swedish Research Council (VR)|621-2005-3245621-2008-3222623-2009-7348|Swedish Foundation for Strategic Research||</p

Growth of TiC/a-C:H nanocomposite films by reactive high power impulse magnetron sputtering under industrial conditions Growth of Ti-C nanocomposite films by reactive high power impulse magnetron sputtering under industrial conditions

Abstract Titanium carbide (TiC) films were deposited employing high power impulse magnetron sputtering (HiPIMS) and direct current magnetron sputtering (DCMS) in an Ar-C 2 H 2 atmosphere of various compositions. Analysis of the structural, bonding and compositional characteristics revealed that the deposited films are either TiC and hydrogenated amorphous carbon (a-C:H) nanocomposites, nanocrystalline TiC, or Ti/TiC, depending on the C/Ti ratio. It was found that Ti-C films grown by HiPIMS show a C/Ti ratio of close to 1 for a wide C 2 H 2 flow range (4-15 sccm), with free C ranging from 0 to 20%. Thus, films ranging from near stoichiometric single phase TiC to TiC/a-C:H nanocomposites can be synthesized. This was not the case for DCMS, where films grown using similar deposition rates as for HiPIMS *Manuscript Click here to view linked References 2 formed larger fractions of amorphous C matrix, thus being nanocomposites in the same C 2 H 2 (above 4 sccm) flow range. For a C/Ti ratio of 1 the resistivity is low (4-8×10 2 µΩcm) for the HiPIMS films, and high (&gt;100×10 2 µΩcm) for the DCMS films. The hardness also shows a big difference with 20-27 and 6-10 GPa for HiPIMS and DCMS grown films, respectively

Growth of TiC/a-C:H nanocomposite films by reactive high power impulse magnetron sputtering under industrial conditions

Titanium carbide (TiC) films were deposited employing high power impulse magnetron sputtering (HiPIMS) and direct current magnetron sputtering (DCMS) in an Ar-C2H2 atmosphere of various compositions. Analysis of the structural, bonding and compositional characteristics revealed that the deposited films are nanocomposites; either hydrogenated amorphous carbon and TiC (TiC/a-C:H), or Titanium and TiC (Ti/TiC) depending on the C/Ti ratio of the films. It was found that TiC/a-C:H films grown by HiPIMS were dense, and within a certain C2H2 flow range (4-15 sccm) showed little changes in C/Ti ratio, which also saturated towards 1. The HiPIMS grown films also exhibited the tendency to form smaller fractions of amorphous C matrix, and incorporate smaller amounts of oxygen contaminants, as compared to films grown by DCMS. The TiC/a-C:H films exhibited resistivity and hardness values of 4-8×102 μΩcm and 20-27 GPa, respectively when deposited by HiPIMS. The corresponding values for films grown by DCMS at the same deposition rate as HiPIMS were &gt;10×102 μΩcm and ~6-10 GPa respectively, likely due to abundant formation of free C and porosity, allowing oxygen contaminations.funding agencies|Swedish Research Council (VR)| 621-2005-3245 621-2008-3222 623-2009-7348 |</p

Growth of TiC/a-C:H nanocomposite films by reactive high power impulse magnetron sputtering under industrial conditions

Titanium carbide (TiC) films were deposited employing high power impulse magnetron sputtering (HiPIMS) and direct current magnetron sputtering (DCMS) in an Ar-C2H2 atmosphere of various compositions. Analysis of the structural, bonding and compositional characteristics revealed that the deposited films are nanocomposites; either hydrogenated amorphous carbon and TiC (TiC/a-C:H), or Titanium and TiC (Ti/TiC) depending on the C/Ti ratio of the films. It was found that TiC/a-C:H films grown by HiPIMS were dense, and within a certain C2H2 flow range (4-15 sccm) showed little changes in C/Ti ratio, which also saturated towards 1. The HiPIMS grown films also exhibited the tendency to form smaller fractions of amorphous C matrix, and incorporate smaller amounts of oxygen contaminants, as compared to films grown by DCMS. The TiC/a-C:H films exhibited resistivity and hardness values of 4-8×102 μΩcm and 20-27 GPa, respectively when deposited by HiPIMS. The corresponding values for films grown by DCMS at the same deposition rate as HiPIMS were &gt;10×102 μΩcm and ~6-10 GPa respectively, likely due to abundant formation of free C and porosity, allowing oxygen contaminations.funding agencies|Swedish Research Council (VR)| 621-2005-3245 621-2008-3222 623-2009-7348 |</p

Influence of ionization degree on film properties when using high power impulse magnetron sputtering

Chromium thin films are deposited by combining direct current magnetron sputtering and high power impulse magnetron sputtering (HiPIMS) on a single cathode in an industrial deposition system. While maintaining a constant deposition rate and unchanged metal ion energy distribution function, the fraction of the total power supplied by either deposition technique is altered, and thereby also the metal ion to metal neutral ratio of the deposition flux. It is observed that the required total average power needed to be proportionally increased as the HiPIMS fraction is increased to be able to keep a constant deposition rate. The influence on microstructure, electrical, and electrochemical properties of the films is investigated and shows improvements with the use of HiPIMS. However, considerable influence of the studied properties occurs already when only some 40% of the total power is supplied by the HiPIMS technique. Further increase of the HiPIMS power fraction results in comparatively minor influence of the studied properties yet significant deposition rate efficiency reduction. The results show that the degree of ionization can be controlled separately, and that the advantages associated with using HiPIMS can be obtained while much of the deposition rate reduction, often reported for HiPIMS, can be avoided.Funding Agencies|Swedish Research Council (VR)|621-2005-3245621-2008-3222623-2009-7348|Swedish Foundation for Strategic Research||</p

Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction

Abstract Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstrac