| 1. |
- Davidsson, Lisa
(författare)
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Priming and activation of neutrophils from blood and tissue
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammation is a powerful process, involved in many disease states, as well as in physiological situations. Neutrophils, the main characters of this thesis, are potent immune cells with the capacity to regulate inflammatory responses. In health, circulating blood neutrophils are regarded as quiescent, with limited responsiveness to stimuli. When needed to combat infection, or during, e.g., flares of inflammatory disease, neutrophils have to leave the circulation to reach the inflamed tissue. The process of passing through, i.e., transmigrate, the blood vessel wall is believed to functionally alter and pre-activate the neutrophils, an event referred to as priming. Primed neutrophils are able to respond forcefully to activating stimuli, including the performance of efficient phagocytosis, maximal release of microbicidal molecules, production of reactive oxygen species (ROS) and formation of neutrophil extracellular traps (NETs). In certain disease states also circulating blood neutrophils can be primed, due to the presence of, e.g., proinflammatory cytokines or bacterial products in the bloodstream. While properly regulated priming of tissue neutrophils is beneficial for fighting bacteria, priming of neutrophils in the circulation often results in adverse outcomes, since uncontrolled neutrophil activation can damage the surrounding vasculature. Priming is thus to be seen as a control mechanism, important in the regulation of neutrophil activation. Despite tissue neutrophils being the main effector cells, blood neutrophils represent the main source of knowledge on neutrophil biology, due to the simplicity of obtaining these cells. The overall aim of this thesis was to increase the current knowledge on neutrophil priming and activation, complex processes that participate in regulating inflammation, in blood and tissue, in health as well as in inflammatory disease. In paper I, a simple skin blister technique to obtain and study in vivo transmigrated neutrophils was described and characterized. In paper II, in contrast to neutrophils obtained from skin blisters and skin chambers (two in vivo models of aseptic inflammation) and the leading dogma, synovial fluid neutrophils derived from patients with inflammatory arthritis were shown to display no, or only mild, signs of priming. In paper III, the interactions between neutrophils and monosodium urate (MSU) crystals, triggers of the inflammatory disease gout, were studied. Neutrophil ROS production induced by the crystals was shown to be strictly intracellular and clearly primed in tissue neutrophils derived from skin chambers. NET formation induced by the crystals was not dependent on ROS and not primed in any of the studied tissue neutrophils. In paper IV, blood neutrophils from gout patients were shown to be primed for baseline and MSU crystal triggered ROS production, while NET formation and receptor expression were similar between neutrophils from gout patients and controls. In conclusion, this thesis highlights the complexity of neutrophil priming and activation and the changes that neutrophils undergo during transmigration to different inflamed tissues.
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| 2. |
- Dahlstrand Rudin, Agnes, et al.
(författare)
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The neutrophil subset defined by CD177 expression is preferentially recruited to gingival crevicular fluid in periodontitis
- 2021
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Ingår i: Journal of Leukocyte Biology. - : WILEY. - 0741-5400 .- 1938-3673. ; 109:2, s. 349-362
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, the concept of distinct subpopulations of human neutrophils has attracted much attention. One bona fide subset marker, exclusively expressed by a proportion of circulating neutrophils in a given individual, and therefore dividing neutrophils in two distinct subpopulations, is the glycoprotein CD177. CD177 is expressed on the plasma and granule membranes of 0-100% of circulating neutrophils depending on the donor. Several in vitro studies have linked CD177 to neutrophil transmigration, yet very few have looked at the role of CD177 for tissue recruitment in vivo. We investigate whether the CD177(+)and CD177(-)neutrophil subsets differ in their propensity to migrate to both aseptic- and microbe-triggered inflamed human tissues. Microbe-triggered neutrophil migration was evaluated in samples of gingival crevicular fluid (GCF) from patients with periodontitis, whereas neutrophil migration to aseptic inflammation was evaluated in synovial fluid from patients with inflammatory arthritis, as well as in exudate from experimental skin chambers applied on healthy donors. We found that the proportion of CD177(+)neutrophils was significantly higher in GCF from patients with periodontitis, as compared to blood from the same individuals. Such accumulation of CD177(+)neutrophils was not seen in the two models of aseptic inflammation. Moreover, the proportion of CD177(+)neutrophils in circulation was significantly higher in the periodontitis patient group, as compared to healthy donors. Our data indicate that the CD177(+)neutrophil subset is preferentially recruited to the gingival crevice of periodontitis patients, and may imply that this subtype is of particular importance for situations of microbe-driven inflammation.
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| 3. |
- Davidsson, Lisa, et al.
(författare)
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In Vivo Transmigrated Human Neutrophils Are Highly Primed for Intracellular Radical Production Induced by Monosodium Urate Crystals.
- 2020
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 21:11
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Tidskriftsartikel (refereegranskat)abstract
- Gout is an inflammatory disease caused by monosodium urate (MSU) crystals. The role of neutrophils in gout is less clear, although several studies have shown neutrophil extracellular trap (NET) formation in acutely inflamed joints of gout patients. MSU crystals are known to induce the production of reactive oxygen species (ROS) and NET formation in neutrophils isolated from blood, but there is inconclusive knowledge on the localization of ROS production as well as whether the ROS are required for NET formation. In this report we demonstrate that MSU crystals activate human neutrophils to produce ROS exclusively in intracellular compartments. Additionally, in vivo transmigrated neutrophils derived from experimental skin chambers displayed markedly increased ROS production as compared to resting blood neutrophils. We also confirmed that MSU stimulation potently induced NET formation, but this response was not primed in in vivo transmigrated neutrophils. In line with this we found that MSU-triggered NET formation was independent of ROS production and proceeded normally in neutrophils from patients with dysfunctional respiratory burst (chronic granulomatous disease (CGD) and complete myeloperoxidase (MPO) deficiency). Our data indicate that in vivo transmigrated neutrophils are markedly primed for oxidative responses to MSU crystals and that MSU triggered NET formation is independent of ROS production.
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| 4. |
- Björkman, Lena, 1965, et al.
(författare)
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Neutrophil recruitment to inflamed joints can occur without cellular priming.
- 2019
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Ingår i: Journal of leukocyte biology. - 1938-3673. ; 105:6, s. 1123-1130
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment of neutrophils from blood to tissues is a cardinal event in inflammation during which neutrophils switch from a resting, naive state to a preactivated, primed phenotype; the priming process is characterized by alterations in the composition of cell surface adhesins, for example, shedding of l-selectin and mobilization of granule-stored integrins to the cell surface. Ligation of chemotactic receptors and interactions with the endothelial lining are established triggers of neutrophil priming and in line with this, in vivo transmigrated neutrophils obtained from tissues are typically highly primed. We here characterize the priming of neutrophils brought about by in vivo recruitment from blood to inflamed joints by the analyses of synovial fluid and blood from patients with inflammatory arthritis. For comparisons, we used controlled in vivo models of neutrophil transmigration to skin of healthy subjects. In contrast to the residing view and in vivo transmigrated neutrophils from skin models, neutrophils from synovial fluid were often surprisingly resting and phenotypically very similar to naive cells isolated from peripheral blood; synovial fluid cells often retained l-selectin and had undergone minimal up-regulation of integrin receptors. In complete agreement with our in vivo findings, cell-free synovial fluid was potently chemotactic without triggering alteration of surface receptors also in vitro. We conclude that tissue recruitment of neutrophils does not by default trigger l-selectin shedding and granule mobilization, and the chemoattractant(s) guiding neutrophils to synovial fluid apparently operate without inducing cellular priming.
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| 5. |
- Christenson, Karin, et al.
(författare)
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Collection of in vivo transmigrated neutrophils from human skin.
- 2014
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Ingår i: Methods in molecular biology (Clifton, N.J.). - Totowa, NJ : Humana Press. - 1940-6029. ; 1124, s. 39-52
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Forskningsöversikt (refereegranskat)abstract
- A wealth of knowledge on the life and death of human neutrophils has been obtained by the in vitro study of isolated cells derived from peripheral blood. However, neutrophils are of main importance, physiologically as well as pathologically, after they have left circulation and transmigrated to extravascular tissues. The journey from blood to tissue is complex and eventful, and tissue neutrophils are in many aspects distinct from the cells left in circulation. Here we describe how to obtain human tissue neutrophils in a controlled experimental setting from aseptic skin lesions created by the application of negative pressure. One protocol enables the direct analysis of the blister content, infiltrating leukocytes as well as exudate fluid, and is a simple method to follow multiple parameters of aseptic inflammation in vivo. Also described is the skin chamber technique, a method based on denuded skin blisters which are subsequently covered by collection chambers filled with autologous serum. Although slightly more artificial as compared to analysis of the blister content directly, the cellular yield of this skin chamber method is sufficient to perform a large number of functional analyses of in vivo transmigrated cells.
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| 6. |
- Davidsson, Lisa, et al.
(författare)
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A simple skin blister technique for the study of in vivo transmigration of human leukocytes.
- 2013
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Ingår i: Journal of immunological methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 393:1-2, s. 8-17
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Tidskriftsartikel (refereegranskat)abstract
- The study of human leukocytes is almost exclusively conducted using cells isolated from peripheral blood. This is especially true for neutrophils, despite the fact that these cells are of main (pathological) importance in extravascular tissues upon e.g., infection and/or tissue damage. The journey from circulation to tissue is typically associated with a number of cellular changes, making the cells primed, or hyper-responsive, and in many aspects distinct from the cells present in circulation. Models to obtain in vivo transmigrated leukocytes from human tissue are available, but not widely used. We describe here an easy-to-use model for the study of local inflammation, stemming from limited tissue damage, which can be used to isolate viable and functional leukocytes. The model is based on the generation of aseptic skin blisters, formed by the application of negative pressure, and allows for investigations of the cellular infiltrate as well as of soluble mediators present in the exudate. We believe that this method, combined with modern analysis equipment suitable for small volumes and cell numbers, could be of great use for increasing our understanding of the nature and function of leukocytes that have left circulation and transmigrated to inflamed tissues.
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| 7. |
- Davidsson, Lisa, et al.
(författare)
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Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up.
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To examine if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases. METHODS: Plaque occurrence in both carotid arteries, and in the right femoral artery were assessed at baseline by B-mode ultrasound in a population-based sample of 58-year-old men (n=391) with no cardiovascular disease, and varying degrees of obesity and insulin sensitivity at entry. Anthropometry and blood pressure were recorded. Fasting venous blood samples were used for measurement of cardiovascular risk factors. Cardiovascular events occurring during follow-up were obtained by access to register data. RESULTS: Systolic blood pressure, serum triglycerides and waist-hip ratio as well as baseline occurrence of carotid and femoral plaques were associated with events. Logistic multi-variate analyses showed that carotid plaques (OR 2.09, 95% CI 1.05-4.16, p=0.037), femoral plaques (OR 1.99, 95% CI 1.01-3.91, p=0.047) and concomitant presence of carotid, and femoral plaques (OR 2.53, 95% CI 1.23-5.21, p=0.011) were associated with cardiovascular events independently of other risk factors. Plaques occurred in 0-3 arteries and there was a parallel increase in cardiovascular risk (p=0.004). CONCLUSION: Occurrence of carotid or femoral plaques at baseline had similar predictive value for cardiovascular events. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk.
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| 8. |
- Bergqvist, Inger, et al.
(författare)
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Utveckling av ett instrument för vårdtyngdsmätning inom anestesi
- 2003
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Ingår i: Vård i Norden. - : Sykepleiernes Samarbeid i Norden. - 0107-4083. ; 23:3, s. 10-15
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Tidskriftsartikel (refereegranskat)abstract
- Patient classification in anaesthetic care is an undeveloped field and it is therefore urgent to construct an instrument for this purpose. The aim of the study was to develop an instrument to measure anaesthetic nursing care with focus on the unique care needed by every single patient. The Delphi technique was used. The method involved five series of inquiries to a panel of experts, consisting of ten nurses. The instrument developed, included 13 nursing care areas, with predefined alternatives graded from1 to 4, where 4 indicated high workload, and 1 indicated low workload. The instrument was tested in a pilot study and showed agreement with the clinical picture of the patients needs. An initial inter-rater reliability test showed very good agreement for all the nursing care areas. The instrument, however, needs to be tested for validity and reliability in a larger sample.
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