| 1. |
- Gautam, Narinder, et al.
(författare)
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Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability
- 2001
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:10, s. 1123-1127
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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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| 2. |
- Gautam, Narinder, et al.
(författare)
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Signaling via β2 integrins triggers neutrophil-dependent alteration in endothelial barrier function
- 2000
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 191:11, s. 1829-1839
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Tidskriftsartikel (refereegranskat)abstract
- Activation of polymorphonuclear leukocytes (PMNs) and adhesion to the endothelial lining is a major cause of edema formation. Although known to be dependent on the function of β2 integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by β2 integrins in PMN-induced alterations in tight junctional permeability of cultured endothelial cell (EC) monolayers was investigated. PMN activation, in the absence of proinflammatory stimuli, was accomplished through antibody cross- linking of CD11b/CD18, mimicking adhesion-dependent receptor engagement. CD18 cross-linking in PMNs added to the EC monolayer provoked a prompt increase in EC permeability that coincided with a rise in EC cytosolic free Ca2+ and rearrangement of actin filaments, events similar to those evoked by chemoattractant PMN activation. Cell-free supernatant obtained after CD18 cross-linking in suspended PMNs triggered an EC response indistinguishable from that induced by direct PMN activation, and caused clear-cut venular plasma leakage when added to the hamster cheek pouch in vivo preparation. The PMN-evoked EC response was specific to β2 integrin engagement inasmuch as antibody cross-linking of L-selectin or CD44 was without effect on EC function. Our data demonstrate a causal link between outside-in signaling by β2 integrins and the capacity of PMNs to induce alterations in vascular permeability, and suggest a paracrine mechanism that involves PMN-derived cationic protein(s) in the cellular crosstalk between PMNs and ECs.
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| 3. |
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| 4. |
- Johansson, Joakim, et al.
(författare)
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Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2:FiO(2) Ratio Early After Major Burns
- 2015
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Ingår i: Journal of Burn Care & Research. - : Lippincott Williams & Wilkins. - 1559-047X .- 1559-0488. ; 36:4, s. 484-492
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Tidskriftsartikel (refereegranskat)abstract
- Leukocytes are activated systemically and their numbers increase soon after a burn followed by a rapid decline to low normal or subnormal levels, possibly by increased extravasation. Experimental data support that an important target for such extravasation is the lungs and that leukocytes when they adhere to endothelial cells cause an increase in vascular permeability. The authors investigated a possible relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO(2) ratio and the dynamic change in concentration of blood leukocytes after a burn. This is a prospective, exploratory, single-center study. The authors measured the dynamic changes of leukocytes in blood starting early after the burn, pulmonary vascular permeability index by thermodilution, and PaO2:FiO(2)-ratios in 20 patients during the first 21 days after a major burn (greater than20% TBSA%). Median TBSA was 40% interquartile range (IQR, 25-52) and full thickness burn 28% (IQR, 2-39). There was a correlation between the early (less than24 hours) alteration in white blood cell count and both early increased pulmonary vascular permeability (r = .63, P = .004) and the decreased oxygenation index defined as PaO2:FiO(2) less than 27 kPa (P = .004). The authors have documented a correlation between dynamic change of blood leukocytes and pulmonary failure early after burns.
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| 5. |
- Johansson, Joakim, et al.
(författare)
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Dynamics of leucocytes correlate with increased pulmonary vascular permeability and decreased PaO2:FiO2 ratio early after major burns
- 2009
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The lung is affected soon after a major burn as indicated by a decreased PaO2:FiO2 ratio. The exact mechanism underlying this is not known. Polymorphonuclear leucocytes (PMN) are activated systemically and their numbers are largely increased soon after a burn followed by a rapid decline to low normal or subnormal numbers within 24 hours, possibly by increased extravasation. Experimental data have supported the hypothesis that an important target for this extravasation is the lungs. Other studies also show that when PMN adhere to endothelial cells they increase vascular permeability, and this effect is mediated, at least in part, by release of heparin binding protein (HBP, also known as CAP-37 and azurocidin). We hypothesised that there is a relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO2 ratio and the dynamic change in blood leucocytes after a burn, possibly mediated by the local release of HBP.Material and methods: This is a prospective, descriptive, exploratory, singlecentre study at a national burn centre. We investigated the dynamic changes of leucocytes in blood, plasma concentrations of HBP, pulmonary vascular permeability index (PVPI) by thermodilution, and PaO2:FiO2 ratios in 20 patients during the first 21 days after a major burn (20% >total burn surface area %).Results: Median total burn surface area was 40% (IQR 25-52) and full thickness burn 28% (IQR 2-39). There was a correlation between the early (<24 hours) alteration in circulating white blood cell count and both early increased vascular permeability in the lung (r=0.63, p=0.004) and the decreased oxygenation index defined as PaO2:FiO2 < 27 kPa (p=0.004). There were no associations between plasma concentrations of HBP and measured pulmonary vascular permeability or PaO2:FiO2 ratios.Conclusions: The results indicate that trapping of leucocytes in the lung may be an important factor in early increased pulmonary vascular permeability and decrease of the PaO2:FiO2 ratio. Our data do not support the idea that HBP, assessed by systemic plasma concentrations, mediate this effect.
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| 6. |
- Johansson, Joakim, 1973-
(författare)
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Function of granulocytes after burns and trauma, associations with pulmonary vascular permeability, acute respiratory distress syndrome, and immunomodulation
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Our innate immunesystem protects us from infections but, since its methods is not all specific for microorganisms, may also induce collateral damage.Severe physical injury often proved deadly throughout evolution. Such injuries may induce massive collateral damage. Nowadays we can initiate advanced critical care for affected patients and save them from imminent trauma-related death. We are therefore faced with the fact that the collateral damage from the immune system may pose a major threat to the patient, the pathophysiology of which is not amenable to direct medical treatment and which leaves us with only passive supportive measures.In this thesis we investigated the role of leucocytes under such circumstances.Our main aim was to understand better the role of leucocytes in the development of increased vascular permeability after burns and trauma.More specifically we investigated the impact of an injury on the function of leucocytes such as the dynamic change of certain cell-surface receptors on the leucocytes and in their numbers and immature forms. We wanted to find out if the increased pulmonary vascular permeability after a burn could be mediated through heparin binding protein (HBP) released from granuloctes, and whether HBP could be used as a biomarker for respiratory failure after trauma. We also wanted to confirm the possible role of histamine as a mediator of the systemic increase in vascular permeability after burns.Methods: The dynamic change of cell-surface receptors was measured by flow-acquired cytometer scanning (FACS) on blood samples taken after burns. The concentrations of HBP after a burn and mechanical trauma were analysed in plasma. Pulmonary vascular permeability after a burn was assessed using transpulmonary thermodilution. The histamine turnover after a burn was assessed with high performance liquid chromatography (HPLC) for concentrations of histamine and methylhistamine in urine.Results: We confirmed earlier investigations showing altered expression of receptors on leucocytes after a burn, receptors intimately associated with leucocyte functions (study I). In a pilot study of 10 patients we measured plasma concentrations of HBP and found them to be increased soon after a burn (study II). This finding was not confirmed in a larger, more extensive and specific study of 20 patients. We did, however, find an association between alterations in the number of leucocytes soon after a burn and pulmonary vascular permeability, indicating that they had a role in this process (study III).In another study of trauma (non burn) we found an association between the concentration of HBP in early plasma-samples after injury and the development of ARDS, indicating that granulocytes and HBP have a role in its aetiology (study IV).We found a small increase in urinary histamine and normal urinary methylhistamine concentrations but had anticipated a distinct increase followed by a decrease after reading the current papers on the subject. This indicates that the role of histamine as a mediator of increased vascular permeability after burns may have been exaggerated (study V).Conclusions: We conclude that leucocytes are affected by burns and trauma, and it is likely that they contribute to the development of respiratory failure and acute respiratory distress syndrome (ARDS). HBP is a candidate biomarker for the early detection of ARDS after trauma, and the white blood count (WBC) is a useful biomarker for the detection of decreased oxygenation soon after a burn.
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| 7. |
- Johansson, Joakim, et al.
(författare)
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Neutrophil-derived heparin binding protein-A mediator of increased vascular permeability after burns?
- 2009
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Ingår i: BURNS. - : Elsevier BV. - 0305-4179 .- 1879-1409. ; 35:8, s. 1185-1187
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Tidskriftsartikel (refereegranskat)abstract
- Increased vascular permeability and oedema formation constitute a major clinical challenge following burns. Several clinical studies show that leukocytes are systemically activated following burns. Neutrophils have the capability to increase vascular permeability via mechanisms thought to involve the release of heparin binding protein (HBP). We hypothesised that HBP is elevated in plasma after major burns due to a systemic inflammatory response and investigated plasma-HBP concentrations in 10 severely burned patients daily for 1 week following the burn. Five-fold higher levels in plasma-HBP concentration compared to a control group were detected on the first day after injury, followed by a steep reduction in the time-period that corresponds to the last part of the hyperpermeability phase. These data are in accordance with the hypothesis that HBP may function as a mediator of the early bum-induced increase in vascular permeability, and call for further studies to confirm a possible cause-and-effect relationship between HBP and oedema formation following burns.
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| 8. |
- Karlsson, Hanna L, et al.
(författare)
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Comparison of genotoxic and inflammatory effects of particles generated by wood combustion, a road simulator and collected from street and subway
- 2006
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 165:3, s. 203-211
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Tidskriftsartikel (refereegranskat)abstract
- The health effects of exposure to airborne particles are of increasing concern in society. In order to protect public health, a clarification of the toxic properties of particles from different sources is of importance. The aim of this study was to investigate and compare the genotoxicity and the ability to induce inflammatory mediators of nine different particle types from wood and pellets combustion, from tire–road wear and collected from an urban street and a subway station. The comet assay was used to assess genotoxicity after exposure of the human lung cell line A549. Inflammatory effects were measured as induction of IL-6, IL-8 and TNF-α after exposure of human macrophages. We found that all particles tested caused DNA damage and those from the subway caused more damage than the other particles (p < 0.001) likely due to redox-active iron. In contrast, particles collected from an urban street were most potent to induce inflammatory cytokines. Particles from tire–road wear collected using a road simulator were genotoxic and able to induce cytokines. Finally, more effective combustion of wood led to less emission of particles, but those emitted did not show less toxicity in this study.
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| 9. |
- Kaukonen, Kirsi-Maija, et al.
(författare)
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Heparin binding protein in patients with acute respiratory failure treated with granulocyte colony-stimulating factor (filgrastim) - a prospective, placebo-controlled, double-blind study
- 2013
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Ingår i: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Heparin Binding Protein (HBP) is released to blood circulation from activated neutrophils in bacterial infections. It is a potential inducer of vascular leakage and precludes the development of septic shock. Filgrastim induces the production of new neutrophils and modulates their bacterial-killing activity. We evaluated the effect of filgrastim on HBP -concentrations in critically ill patients with acute respiratory failure. Methods: 59 critically ill patients with acute respiratory failure were included in this randomised, double-blind, placebo-controlled study of filgrastim 300 micrograms/day or corresponding placebo for 7 days. Plasma samples were drawn on baseline, day 4 and day 7. HBP -concentrations, absolute leukocyte and neutrophil counts were measured. Results: The median [IQR] HBP concentrations were 23.6 ng/ml [13.9-43.0 ng/ml], 25.1 ng/ml [17.7-35.5 ng/ml] and 15.9 ng/ml [12.6-20.7 ng/ml] in patients receiving filgrastim on baseline, day 4 and day 7, respectively. The HBP concentrations in placebo group were 21.6 ng/ml [16.9-28.7 ng/ml], 13.9 ng/ml [12.0-19.5 ng/ml] and 17.8 ng/ml [13.6-20.9 ng/ml]. At day 4, the filgrastim group had significantly higher HBP -concentrations when compared to placebo group (p < 0.05). No correlation between HBP -concentrations and absolute neutrophil count or P/F -ratios was found. Conclusions: Filgrastim treatment is associated with increased circulating HBP levels compared to placebo, but the absolute neutrophil count or the degree of oxygenation failure did not correlate with the observed plasma HBP concentrations. Trial registration: Clinicaltrials.gov NCT01713309
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| 10. |
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