| 1. |
- Denk, Stephanie, et al.
(författare)
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Complement C5a Functions as a Master Switch for the pH Balance in Neutrophils Exerting Fundamental Immunometabolic Effects
- 2017
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 198:12, s. 4846-4854
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Tidskriftsartikel (refereegranskat)abstract
- During sepsis, excessive activation of the complement system with generation of the anaphylatoxin C5a results in profound disturbances in crucial neutrophil functions. Moreover, because neutrophil activity is highly dependent on intracellular pH (pH(i)), we propose a direct mechanistic link between complement activation and neutrophil pHi. In this article, we demonstrate that in vitro exposure of human neutrophils to C5a significantly increased pHi by selective activation of the sodium/hydrogen exchanger. Upstream signaling of C5a-mediated intracellular alkalinization was dependent on C5aR1, intracellular calcium, protein kinase C, and calmodulin, and downstream signaling regulated the release of antibacterial myeloperoxidase and lactoferrin. Notably, the pH shift caused by C5a increased the glucose uptake and activated glycolytic flux in neutrophils, resulting in a significant release of lactate. Furthermore, C5a induced acidification of the extracellular micromilieu. In experimental murine sepsis, pHi of blood neutrophils was analogously alkalinized, which could be normalized by C5aR1 inhibition. In the clinical setting of sepsis, neutrophils from patients with septic shock likewise exhibited a significantly increased pHi. These data suggest a novel role for the anaphylatoxin C5a as a master switch of the delicate pHi balance in neutrophils resulting in profound inflammatory and metabolic changes that contribute to hyperlactatemia during sepsis.
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| 2. |
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| 3. |
- Bäck, Jennie, et al.
(författare)
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Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces
- 2009
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 30:34, s. 6573-6580
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Tidskriftsartikel (refereegranskat)abstract
- Activated human plate lets trigger FXII-mediated contact activation, which leads to the generation of FXIIa-antithrombin (AT) and FXIa-AT complexes. This suggests that contact activation takes place at different sites, on activated platelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa-C1INH and KK-C1INH, and almost no AT complexes. Platelet activation, in both PRP and blood, led to the formation of FXIIa-AT, FXIa-AT, and kallikrein (KK)-AT but almost no C1INH complexes. In severe trauma patients, FXIIa-AT and FXIa-AT were correlated with the release of thrombospondin-1 (TSP-1) from activated platelets. In contrast, FXIIa-C1INH complexes were detected when the FXIIa-AT levels were low. No correlations were found between FXIIa-C1INH and FXIIa-AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa-AT and FXIIa-C1INH complexes can help to distinguish between contact activation triggered by biomaterial surfaces and by activated platelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contact activation and that generation of FXIIa-AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices.
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| 4. |
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| 5. |
- Halbgebauer, Rebecca, et al.
(författare)
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Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and apost hocanalysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney.In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550,). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically,in vitrodata suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibitionin vivomay inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.
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| 6. |
- Harrad, Stuart, et al.
(författare)
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Indoor Contamination with Hexabromocyclododecanes, Polybrominated Diphenyl Ethers, and Perfluoroalkyl Compounds : An Important Exposure Pathway for People?
- 2010
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 44:9, s. 3221-3231
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Forskningsöversikt (refereegranskat)abstract
- This review underlines the importance of indoor contamination as a pathway of human exposure to hexabromocyclododecanes (HBCDs), polybrominated diphenyl ethers (PBDEs), and perfluoroalkyl compounds (PFCs). There is ample evidence of substantial contamination of indoor dust with these chemicals and that their concentrations in indoor air exceed substantially those outdoors. Studies examining the relationship between body burden and exposure via indoor dust are inconsistent while some indicate a link between body burdens and PBDE and HBCD exposure via dust ingestion, others find no correlation. Likewise, while concentrations in indoor dust and human tissues are both highly skewed, this does not necessarily imply causality. Evidence suggests exposure via dust ingestion is higher for toddlers than adults. Research priorities include identifying means of reducing indoor concentrations and indoor monitoring methods that provide the most ""biologically-relevant"" measures of exposure as well as monitoring a wider range of microenvironment categories. Other gaps include studies to improve understanding of the following: emission rates and mechanisms via which these contaminants migrate from products into indoor air and dust; relationships between indoor exposures and human body burdens; relevant physicochemical properties; the gastrointestinal uptake by humans of these chemicals from indoor dust; and human dust ingestion rates.
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| 7. |
- Hochstöger, Daniel, et al.
(författare)
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Experiences from commissioning and first operation of a 1 mw demonstration-scale dual fluidized bed gasification plant
- 2023
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Ingår i: European biomass conference and exhibition proceedings. - : ETA-Florence Renewable Energies. ; , s. 594-599
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Konferensbidrag (refereegranskat)abstract
- The use of biomass, whether wood or waste materials, represents an opportunity to reduce dependence on fossil fuels. Using dual fluidized bed (DFB) steam gasification technology for conversion of biomass, biogenic residues and waste is a possible approach to exploit this potential. A demonstration-scale 1 MW gasification plant with subsequent product gas and flue gas cleaning has been constructed at the Syngas Platform Vienna. The performance of this plant during its first continuous operation was evaluated in this study by analyzing temperature and pressure profiles recorded over a period of nearly 6 hours of continuous operation and by evaluating various performance indicators, such as steam-to-fuel ratio, gasification temperatures, and product gas composition. The resulting data sets were compared with existing results from the 100 kW pilot plant at TU Wien. The discrepancies found and their avoidance is discussed. In addition, this paper highlights the mechanical challenges encountered during commissioning, such as high temperatures at the fabric filter and additional condensate drain in steam supply pipes, and identifies potential challenges during the installation and operation of future gasification plants.
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| 8. |
- Huber, Miriam, et al.
(författare)
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Tar conversion and recombination in steam gasification of biogenic residues : the influence of a countercurrent flow column in pilot- and demonstration-scale
- 2024
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Ingår i: Fuel. - : Elsevier. - 0016-2361 .- 1873-7153. ; 364
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Tidskriftsartikel (refereegranskat)abstract
- First experiments with biogenic residues and a plastic-rich rejects and woody biomass blend were conducted in an advanced 1 MW dual fluidized bed steam gasification demonstration plant at the Syngas Platform Vienna. Wood chips, bark, forest residues, and the plastic-rich rejects and woody biomass blend were tested and the tar composition was analyzed upstream and downstream of the upper gasification reactor, which is designed as a high-temperature column with countercurrent flow of catalytic material. Each feedstock was gasified with olivine as bed material in demonstration scale and is compared to the gasification of softwood pellets with olivine and limestone in pilot scale. A reduction in tar content was observed after countercurrent column for all feedstocks. However, a shift in tar species occurred. While styrene, phenol, and 1H-indene were predominant upstream, naphthalene and polycyclic aromatic hydrocarbons (PAHs) were the prevailing tar species downstream the countercurrent column. Hence, an increase of i.e. anthracene, fluoranthene, and pyrene from the upstream concentration was observed. For pyrene, up to twice the initial concentration was measured. This recombination to PAHs was observed for all feedstocks in demonstration- and pilot-scale. The only exception occurred with limestone as bed material, characterized by a higher catalytic activity in comparison to the typically used olivine. In the perspective of the integrated product gas cleaning, tar with higher temperature of condensation are separated more efficiently in the installed scrubbing unit. Hence, the recombination facilitates an overall decline of tar content after the gas cleaning.
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| 9. |
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| 10. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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