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Sökning: WFRF:(Herwald H)

  • Resultat 1-10 av 49
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1.
  • Halldorsdottir, H. D., et al. (författare)
  • Heparin-binding protein as a biomarker of post-injury sepsis in trauma patients
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley-Blackwell. - 0001-5172 .- 1399-6576. ; 62:7, s. 962-973
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Heparin-binding protein (HBP) is a neutrophil-derived protein advocated as a biomarker in sepsis. We evaluated plasma HBP as a predictor of post-injury sepsis in trauma patients. Methods: Ninety-seven trauma patients were studied during the first week of intensive care. Injury-related data were collected and clinical parameters registered daily. Plasma HBP was sampled on day 1, 3 and 5 after trauma and evaluated for associations with injury-related parameters and sepsis. The predictive properties of HBP were compared to C-reactive protein (CRP) and white blood cell count (WBC). Results: Median Injury Severity Score was 33, one-third of the trauma patients received massive transfusion and a quarter was in shock on arrival. Overall 30-day mortality was 8%. Plasma HBP was significantly higher in severely injured patients and associated with shock on arrival, massive transfusions and organ failure. Septic patients had higher levels of HBP only on day 5. When evaluated for prediction of onset of sepsis during the two following days after plasma sampling by receiver operating characteristic (ROC) analyses, areas under the curves were non-significant for all time points. Similar patterns were seen for CRP and WBC. Conclusion: In trauma patients, HBP levels are related to severity of injury and organ dysfunction. Heparin-binding protein was weakly associated with sepsis and only at the later stage of the observation period of 1 week. Moreover, HBP showed poor discriminatory properties as an early biomarker of post-injury sepsis. Trauma-induced inflammation during the post-injury phase may blunt the sepsis-predictive performance of HBP.
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3.
  • Persson, B. P., et al. (författare)
  • Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?
  • 2014
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley-Blackwell Publishing Ltd. - 0001-5172 .- 1399-6576. ; 58:5, s. 549-559
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundVascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions. MethodsSixteen anesthetized pigs were subjected to 5h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c. ResultsEndotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP. ConclusionsET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.
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4.
  • Bengtson, Sara H, et al. (författare)
  • Kinin receptor expression during Staphylococcus aureus infection.
  • 2006
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 108:6, s. 2055-2063
  • Tidskriftsartikel (refereegranskat)abstract
    • An inappropriate host response to invading bacteria is a critical parameter that often aggravates the outcome of an infection. Staphylococcus aureus is a major human Gram-positive pathogen that causes a wide array of community- and hospital-acquired diseases ranging from superficial skin infections to severe conditions such as staphylococcal toxic shock. Here we find that S aureus induces inflammatory reactions by modulating the expression and response of the B1 and B2 receptors, respectively. This process is initiated by a chain of events, involving staphylococcal-induced cytokine release from monocytes, bacteria-triggered contact activation, and conversion of bradykinin to its metabolite desArg9bradykinin. The data of the present study implicate an important and previously unknown role for kinin receptor regulation in S aureus infections.
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5.
  • Gautam, Narinder, et al. (författare)
  • Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability
  • 2001
  • Ingår i: Nature Medicine. - : Nature Publishing Group. - 1546-170X .- 1078-8956. ; 7:10, s. 1123-1127
  • Tidskriftsartikel (refereegranskat)abstract
    • Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory diseasecauses increased vascular permeability and edema formation through unknown mechanisms.Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration inendothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining,leukocytic 2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein(HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophilcationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gapformation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvesselsin vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducingendothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derivedHBP in the vascular response to neutrophil trafficking in inflammation. Targeting this moleculein inflammatory disease conditions offers a new strategy for prevention of endothelial barrierdysfunction caused by misdirected leukocyte activation.
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6.
  • Papareddy, P., et al. (författare)
  • A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
  • 2019
  • Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 4:12, s. 2442-2455
  • Tidskriftsartikel (refereegranskat)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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7.
  • Snäll, Johanna, et al. (författare)
  • Differential neutrophil responses to bacterial stimuli: Streptococcal strains are potent inducers of heparin-binding protein and resistin-release.
  • 2016
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 6
  • Tidskriftsartikel (refereegranskat)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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8.
  • Berkestedt, Ingrid, et al. (författare)
  • Early depletion of contact system in patients with sepsis : a prospective matched control observational study
  • 2018
  • Ingår i: APMIS. - : John Wiley and Sons. - 0903-4641. ; 126:12, s. 892-898
  • Tidskriftsartikel (refereegranskat)abstract
    • Activation of the contact system generates bradykinin from high-molecular-weight kininogen and has been suggested to participate in the pathophysiology of sepsis. To test this, we prospectively measured bradykinin and high-molecular-weight kininogen levels in a cohort of sepsis patients requiring intensive care. From 29 patients meeting criteria for sepsis or septic shock according to Sepsis-3, blood was sampled within 24 h and on the fourth day following admittance to intensive care. Patients planned for neurosurgery served as matched controls. Sequential organ failure assessment score and 90-day mortality was registered. Bradykinin levels (median [interquartile range]) were lower in sepsis patients (79 [62–172] pg/ml) compared to controls (130 [86–255] pg/ml, p < 0.025) and did not correlate with mortality or severity of circulatory derangement. High-molecular-weight kininogen levels were lower in sepsis patients (1.6 [0.8–4.8] densitometry units) compared to controls (4.4 [2.9–7.7] densitometry units, p < 0.001), suggesting previous contact system activation. High-molecular-weight kininogen levels were lower in non-survivors than survivors (p = 0.003) and negatively correlated to severity of circulatory derangement. We conclude that a role for bradykinin in later stages of severe sepsis must be challenged. Low high-molecular-weight kininogen concentrations suggest that the decrease in bradykinin is due to substrate depletion.
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9.
  • Hasan, A. A.K., et al. (författare)
  • Mapping the cell binding site on high molecular weight kininogen domain 5
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 0021-9258. ; 270:33, s. 19256-19261
  • Tidskriftsartikel (refereegranskat)abstract
    • Investigations mapped the region(s) on the light chain of high molecular weight kininogen (HK) that participates in cell binding. Sequential and overlapping peptides of domain 5 (D5(H)) were synthesized to determine its cell binding site(s). Three peptides from non-overlapping regions on D5(H) were found to inhibit biotin-HK binding to endothelial cells. Peptides GKE19 and HNL21 weakly inhibited biotin-HK binding with IC50 of 792 and 215 μM, respectively. Peptide HKH20 inhibited biotin-HK binding with an IC50 of 0.2 μM. Two peptides, GGH18 and HVL24, which overlapped HKH20, also inhibited biotin-HK binding to endothelial cells with IC50 values of 108 and 0.8 μM, respectively. Biotinylated HKH20 directly bound to endothelial cells. HK and HKH20 bound at or near the same site on endothelial cells because HK inhibited biotin-HKH20 binding (IC50 = 0.2 μM). A polyclonal anti-HKH20 antibody also blocked biotin-HK binding. Peptides HKH20 and HVL24 and anti- HKH20 antibody also inhibited the procoagulant activity of plasma HK. These data indicated that the cell and artificial surface binding sites on D5(H) overlap. The orientation of HK on endothelial cells may be critical for the assembly and activation of contact system enzymes and the expression of kininogen's anti-thrombin activity.
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10.
  • Herwald, H., et al. (författare)
  • Identification of an endothelial cell binding site on kininogen domain D3
  • Ingår i: Journal of Biological Chemistry. - : ASBMB. - 0021-9258. ; 270:24, s. 14634-14642
  • Tidskriftsartikel (refereegranskat)abstract
    • High and low molecular mass kininogen, two multidomain plasma proteins, bind to endothelial cells, platelets, and neutrophils in the intravascular compartment. The specific cell attachment site on their common heavy chain is mediated by domain-3, a cystatin-like structure with inhibitory capacity for papain-like proteinases (Jiang, Y., Muller-Esterl, W., and Schmaier, A. H. (1992) J. Biol. Chem. 267, 3712-3717). In this report, the domain-3 cell binding site is determined by an antibody-directed strategy. The epitope of monoclonal antibody HKH15, which binds to domain-3 and blocks the binding of kininogens to platelets and endothelial cells, was mapped using seven synthetic peptides, which span the entire domain-3 sequence. One peptide, LDC27, specifically bound to HKH15. Fine mapping of the epitope of HKH15 revealed that a minimal 13-residue segment in LDC27, named CNA13, is the antibody binding site. LDC27 and CNA13 inhibited biotinylated high molecular mass kininogen binding to endothelial cells with apparent IC50 values of 60.3 ± 12 and 113.3 ± 63.7 μM, respectively. Carboxymethylated papain and affinity-purified anti-LDC27 polyclonal antibodies also inhibited the binding of biotinylated high molecular mass kininogen to endothelial cells with an apparent IC50 of 1.04 μM and 59 nM, respectively. Biotinylated LDC27 itself directly bound to endothelial cells, and domain-3 inhibited biotinylated LDC27 binding to human umbilical vein endothelial cells with an IC50 of 41 nM. Using the crystalline structure of cystatin to computer model domain-3, LDC27 and CNA13 were located in the second hairpin loop of the reactive site of cystatin-like proteins (Bode, W., Engh, R., Musil, D., Thiele, U. Huber, R., Karshikov, A., Brzin, J., Kos, J., and Turk, V. (1988) EMBO J. 7, 2593-2599). These results indicate that the major endothelial cell attachment site on kininogen domain-3 is located on its carboxyl-terminal portion and that it overlaps its cysteine protease inhibitory region.
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