| 1. |
- Papareddy, Praveen, et al.
(author)
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A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
- 2019
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In: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:12, s. 2442-2455
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Journal article (peer-reviewed)abstract
- Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-kappa B. We found that the modulating effect is primarily restricted to the less abundant beta-isoform (h beta AT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of h beta AT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or h beta AT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with h beta AT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.
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| 2. |
- Chew, Michelle, et al.
(author)
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Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study.
- 2012
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In: Inflammation Research. - : Springer Science and Business Media LLC. - 1420-908X .- 1023-3830. ; 61:4, s. 375-379
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Heparin-binding protein (HBP) is a potent inducer of increased vascular permeability. The purpose of this study was to examine plasma levels of HBP in patients with shock. DESIGN: Fifty-three consecutive patients with septic and non-septic shock at a mixed-bed intensive care unit were included, as well as 20 age-matched controls. Patients with local infections but without signs of shock served as infectious controls. Enzyme-linked immunosorbent assay was used to determine plasma levels of HBP. RESULTS: There were no differences in serum HBP levels between healthy controls and those with local infections, including urinary tract infections, pneumonia and gastroenteritis, without shock. Levels of HBP were higher in patients with non-septic shock and septic shock than healthy controls. However, there was no difference in serum HBP levels between patients with septic shock and those with non-septic shock. Moreover, HBP levels were not different between patients with low and high APACHE II scores. Plasma levels of HBP were similar in surviving and non-surviving patients with shock. CONCLUSIONS: HBP is elevated in patients with shock from septic and non-septic etiologies. Future investigations are required to define the functional role of HBP in patients with shock.
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| 3. |
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| 4. |
- Linder, Adam, et al.
(author)
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Heparin-binding protein: an early marker of circulatory failure in sepsis.
- 2009
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In: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1537-6591 .- 1058-4838. ; 49:7, s. 1044-1050
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Journal article (peer-reviewed)abstract
- BACKGROUND: The early detection of circulatory failure in patients with sepsis is important for successful treatment. Heparin-binding protein (HBP), released from activated neutrophils, is a potent inducer of vascular leakage. In this study, we investigated whether plasma levels of HBP could be used as an early diagnostic marker for severe sepsis with hypotension. METHODS: A prospective study of 233 febrile adult patients with a suspected infection was conducted. Patients were classified into 5 groups on the basis of systemic inflammatory response syndrome criteria, organ failure, and the final diagnosis. Blood samples obtained at enrollment were analyzed for the concentrations of HBP, procalcitonin, interleukin-6, lactate, C-reactive protein, and the number of white blood cells. RESULTS: Twenty-six patients were diagnosed with severe sepsis and septic shock, 44 patients had severe sepsis without septic shock, 100 patients had sepsis, 43 patients had an infection without sepsis, and 20 patients had an inflammatory response caused by a noninfectious disease. A plasma HBP level > or = 15 ng/mL was a better indicator of severe sepsis (with or without septic shock) than any other laboratory parameter investigated (sensitivity, 87.1%; specificity, 95.1%; positive predictive value, 88.4%; negative predictive value, 94.5%). Thirty-two of the 70 patients with severe sepsis were sampled for up to 12 h before signs of circulatory failure appeared, and in 29 of these patients, HBP plasma concentrations were already elevated. CONCLUSION: In febrile patients, high plasma levels of HBP help to identify patients with an imminent risk of developing sepsis with circulatory failure.
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| 5. |
- Malmström, Erik, et al.
(author)
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Targeted mass spectrometry analysis of neutrophil-derived proteins released during sepsis progression.
- 2014
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In: Thrombosis and Haemostasis. - 0340-6245. ; 112:6, s. 1230-1243
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Journal article (peer-reviewed)abstract
- Early diagnosis of severe infectious diseases is essential for timely implementation of lifesaving therapies. In a search for novel biomarkers in sepsis diagnosis we focused on polymorphonuclear neutrophils (PMNs). Notably, PMNs have their protein cargo readily stored in granules and following systemic stimulation an immediate increase of neutrophil-borne proteins can be observed into the circulation of sepsis patients. We applied a combination of mass spectrometry (MS) based approaches, LC-MS/MS and selected reaction monitoring (SRM), to characterise and quantify the neutrophil proteome in healthy or disease conditions. With this approach we identified a neutrophil-derived protein abundance pattern in blood plasma consisting of 20 proteins that can be used as a protein signature for severe infectious diseases. Our results also show that SRM is highly sensitive, specific, and reproducible and, thus, a promising technology to study a complex, dynamic and multifactorial disease such as sepsis.
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| 6. |
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| 7. |
- Oehmcke, Sonja, et al.
(author)
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Treatment of invasive streptococcal infection with a peptide derived from human high molecular weight kininogen.
- 2009
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 114:2, s. 444-451
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Journal article (peer-reviewed)abstract
- Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure due to vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high molecular weight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the pro-inflammatory and pro-coagulant contact system. Activation of the contact system in the bloodstream by S. pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S. pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice.
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| 8. |
- Snäll, Johanna, et al.
(author)
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Differential neutrophil responses to bacterial stimuli: Streptococcal strains are potent inducers of heparin-binding protein and resistin-release.
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- Neutrophils are critical for the control of bacterial infections, but they may also contribute to disease pathology. Here we explore neutrophil responses, in particular the release of sepsis-associated factors heparin-binding protein (HBP) and resistin in relation to specific bacterial stimuli and sepsis of varying aetiology. Analyses of HBP and resistin in plasma of septic patients revealed elevated levels as compared to non-infected critically ill patients. HBP and resistin correlated significantly in septic patients, with the strongest association seen in group A streptococcal (GAS) cases. In vitro stimulation of human neutrophils revealed that fixed streptococcal strains induced significantly higher release of HBP and resistin, as compared to Staphylococcus aureus or Escherichia coli. Similarly, neutrophils stimulated with the streptococcal M1-protein showed a significant increase in co-localization of HBP and resistin positive granules as well as exocytosis of these factors, as compared to LPS. Using a GAS strain deficient in M1-protein expression had negligible effect on neutrophil activation, while a strain deficient in the stand-alone regulator MsmR was significantly less stimulatory as compared to its wild type strain. Taken together, the findings suggest that the streptococcal activation of neutrophils is multifactorial and involves, but is not limited to, proteins encoded by the FCT-locus.
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| 9. |
- Westman, Johannes, et al.
(author)
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Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo.
- 2015
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 11:12
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Journal article (peer-reviewed)abstract
- The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection.
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| 10. |
- Westman, Johannes, et al.
(author)
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Treatment with p33 Curtails Morbidity and Mortality in a Histone-Induced Murine Shock Model.
- 2014
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In: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 6:6, s. 819-830
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Journal article (peer-reviewed)abstract
- Collateral damage caused by extracellular histones has an immediate impact on morbidity and mortality in many disease models. A significant increase in the levels of extracellular histones is seen in critically ill patients with trauma and sepsis. We showed that histones are released from necrotic cells in patients with invasive skin infections. Under in vitro conditions, endogenous p33, an endothelial surface protein also known as the gC1q receptor, interacts with histones released from damaged endothelial cells. Functional analyses have revealed that recombinantly expressed p33 completely neutralizes the harmful features of histones, i.e. hemolysis of erythrocytes, lysis of endothelial cells and platelet aggregation. We also noted that mice treated with a sublethal dose of histones developed severe signs of hemolysis, thrombocytopenia and lung tissue damage already 10 min after inoculation. These complications were fully counteracted when p33 was administered together with the histones. Moreover, application of p33 significantly improved survival in mice receiving an otherwise lethal dose of histones. Together, our data suggest that treatment with p33 is a promising therapeutic approach in severe infectious diseases. © 2014 S. Karger AG, Basel.
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