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  • 1.
    Arinell, Karin
    et al.
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Acute Internal Medicine, Centralsjukhuset, Karlstad, Sweden.
    Blanc, Stéphane
    CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Université de Strasbourg, Strasbourg, France.
    Welinder, Karen Gjesing
    Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
    Støen, Ole Gunnar
    Norwegian Institute for Nature Research, Trondheim, Norway.
    Evans, Alina L.
    Department of Forestry and Wildlife Management, Inland Norway University of Applied Sciences, Koppang, Norway.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Physical inactivity and platelet function in humans and brown bears: A comparative study2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 1, p. 87-90Article in journal (Refereed)
    Abstract [en]

    Physical inactivity increases the risk of thromboembolism. However, good standardized human models on inactivity are in short supply and experimental models are few.

    Our objective was to investigate how standardized bed rest affects platelet aggregation in humans and to investigate if aggregation is altered in a translational model system - the hibernating brown bear (Ursus arctos). We collected blood from (1) healthy male volunteers participating in a 21-day bed rest study in head-down tilt position (-6°) 24 h a day; (2) free-ranging brown bears captured during winter hibernation and again during active state in summer. We analyzed platelet function using multiple electrode platelet aggregometry. In total, 9 healthy male volunteers (age 31.0 ± 6.4 years) and 13 brown bears (7 females and 6 males, age 2.8 ± 0.6 years) were included. In hibernating bears adenosine diphosphate, arachidonic acid, thrombin receptor activating peptide, and collagen impedance aggregometry tests were all halved compared to summer active state. In human volunteers no statistically significant changes were found between baseline and the end of bed rest. In human male volunteers 3 weeks of bed rest did not affect platelet function. In hibernating brown bears platelet aggregation was halved compared to summer and we hypothesize that this is a protective measure to avoid formation of thrombi under periods of low blood flow.

  • 2.
    Arinell, Karin
    et al.
    Dept Cardiol, Örebro Univ Hosp, Örebro, Sweden.
    Fröbert, Ole
    Örebro University Hospital. Dept Cardiol.
    Blanc, Stephane
    Dept Ecol Physiol & Ethol, Dept Ecol, Inst Pluridisciplinaire Hubert Curien, Strasbourg, France.
    Larsson, Anders
    Dept Clin Chem, Uppsala Univ, Uppsala, Sweden.
    Christensen, Kjeld
    Örebro University Hospital. Dept Cardiol.
    Downregulation of platelet activation markers during long-term immobilization2013In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 24, no 5, p. 369-374Article in journal (Refereed)
    Abstract [en]

    Immobilization and sedentary lifestyle are risk factors for venous thromboembolism and cardiovascular disease, yet little is known about platelet function during long-term physical inactivity. Our aim was to investigate platelet activation markers and their coupling to standardized immobilization: platelet-derived growth factor (PDGF-BB) and P-selectin. We studied 15 healthy females participating in the Women International Space simulation for Exploration study. Following a 20-day ambulatory control period, the subjects underwent 60 days of bed rest in head-down tilt position (-6 degrees) 24 hours a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training. Blood samples for the analysis of platelet activation markers were collected at baseline (5 days before bed rest), after 44 days of bed rest and 8 days into the recovery period. Compared to baseline, the levels of P-selectin and PDGF-BB decreased after bed rest (by 55%, p = 0.01 and 73%, p < 0.03, respectively) and remained decreased in the recovery period (by 76%, p < 0.001 and 78%, p < 0.02, respectively, compared to baseline). Platelet count (baseline value for the exercise group 260 000/mu l +/- 34 000 and baseline value for the control group 210 000/mu l +/- 30 000) did not change during the bed rest study (two-way repeated measurements ANOVA, p = ns). There were no statistical differences between the physically inactive and the exercise group. During long-term immobilization, a known risk factor for thrombosis, the levels of P-selectin and PDGF-BB decreased. Our findings indicate downregulation of platelet activation during immobilization.

  • 3.
    Boknäs, Niklas
    et al.
    Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 5, p. 512-519Article in journal (Refereed)
    Abstract [en]

    Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

  • 4.
    Holm, Ann-Charlotte B. Svensson
    et al.
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Pathology and Clinical Genetics, County Council of Östergötland, Linköping, Sweden.
    Ollinger, Karin
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Pathology and Clinical Genetics, County Council of Östergötland, Linköping, Sweden.
    Lindström, Eva G.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function2014In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 25, no 2, p. 111-117Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to investigate the role of 12-lipoxygenase (12-LOX) on platelet-induced airway smooth muscle cell (ASMC) proliferation. Co-incubation of platelets and ASMC caused platelet activation as determined by morphological changes. Simultaneously, reactive oxygen species (ROS)-generation was detected and ASMC proliferation (measured by using the MTS assay) increased significantly. Furthermore, we found that the 12-LOX inhibitors cinnamyl-3,4-dihydroxy-a-cyanocinnamate (CDC) and Baicalein prevented platelet activation in a co-cultures of platelets and ASMC. The inhibitory effect of CDC and Baicalein on platelets was also registered in a pure platelet preparation. Specifically, the 12-LOX inhibitors reduced collagen-induced platelet aggregation both in the presence and absence of external added fibrinogen. Importantly, platelet-induced ASMC proliferation and ROS production generated during the platelet/ASMC interaction was significantly inhibited in the presence of 12-LOX inhibitors. In conclusion, our findings reveal that 12-LOX is crucial for the observed enhancement of ASMC proliferation in co-cultures of platelets and ASMC. The present result suggests that 12-LOX activity is important in the initial step of platelet/ASMC interaction and platelet activation. Such action of 12-LOX represents a potential important mechanism that may contribute to platelet-induced airway remodelling.

  • 5.
    Kälvegren, Hanna
    et al.
    Örebro University, School of Health and Medical Sciences.
    Jonsson, Simon
    Örebro University, School of Health and Medical Sciences.
    Jonasson, Lena
    Örebro University, School of Health and Medical Sciences.
    Release of matrix metalloproteinases-1 and-2, but not-9, from activated platelets measured by enzyme-linked immunosorbent assay2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 8, p. 572-578Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMPs), in particular MMP-9, have been introduced as novel biomarkers in coronary artery disease. Activated platelets are considered to be a major source of the highly elevated levels of MMPs that are detected in serum compared to plasma. The aim of this study was to clarify if activated platelets release MMPs-1, -2 and -9 as measured by enzyme-linked immunosorbent assays (ELISA). Isolated platelets (separated by several procedures) or platelet-rich plasma (PRP) were stimulated by collagen, thrombin or the TLR2 agonist Pam(3)CSK(4). The concentrations of MMPs-1,-2 and -9 in supernatants were determined by ELISA. In addition, a MMP-9 enzyme activity assay was used as well as immunofluorescent staining of MMPs-1,-2 and 9 in platelets. Isolated platelets stimulated by collagen, thrombin or Pam(3)CSK(4) released significant amounts of MMP-1 to the supernatant measured as either pro- or total-MMP-1. However, there was no detectable release of MMP-2 or -9 from isolated platelets. Collagen-stimulated platelets in PRP released MMP-2, but not -9. Before stimulation; platelets were positive for MMPs-1 and -2, but not -9, as assessed by immunofluorescence. Acting as positive controls, neutrophils were found to release significant amounts of MMP-9. Our findings indicate that activated platelets may be a major source of MMP-1 and to a minor extent MMP-2, in peripheral blood. However, in contrast to what has been argued in previous literature, platelets appear to be only negligible contributors to circulating MMP-9.

  • 6.
    Nylander, M
    et al.
    Cardiovascular Inflammation Research Centre, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Sweden; Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden; Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, University Hospital, Linköping, Sweden.
    Lindahl, T L
    Cardiovascular Inflammation Research Centre, Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Sweden.
    Bengtsson, Torbjörn
    Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden.
    Grenegård, M
    Deparment of Medical and Health Science, Division of Pharmacology, Linköping University, Sweden.
    The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine2008In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 5, p. 352-358Article in journal (Refereed)
    Abstract [en]

    Recent studies indicate connections between periodontitis and atherothrombosis, and the periodontal pathogen Porphyromonas gingivalis has been found within atherosclerotic lesions. P. gingivalis-derived proteases, designated gingipains activate human platelets, probably through a "thrombin-like" activity on protease-activated receptors (PARs). However, the potential interplay between P. gingivalis and other physiological platelet activators has not been investigated. The aim of this study was to elucidate consequences and mechanisms in the interaction between P. gingivalis and the stress hormone epinephrine. By measuring changes in light transmission through platelet suspensions, we found that P. gingivalis provoked aggregation, whereas epinephrine alone never had any effect. Intriguingly, pre-treatment of platelets with a low, sub-threshold number of P. gingivalis (i.e. a density that did not directly provoke platelet aggregation) resulted in a marked aggregation response when epinephrine was added. This synergistic action was not inhibited by the cyclooxygenas inhibitor aspirin. Furthermore, fura-2-measurements revealed that epinephrine caused an intracellular Ca(2+) mobilization in P. gingivalis pre-treated platelets, whereas epinephrine alone had no effect. Inhibition of the arg-specific gingipains, but not the lys-specific gingipains, abolished the aggregation and the Ca(2+) response provoked by epinephrine. Similar results were achieved by separate blockage of platelet alpha(2)-adrenergic receptors and PARs. In conclusion, the present study shows that a sub-threshold number of P. gingivalis sensitizes platelets to epinephrine. We suggest that P. gingivalis-derived arg-specific gingipains activates a small number of PARs on the surface of the platelets. This leads to an unexpected Ca(2+) mobilization and a marked aggregation response when epinephrine subsequently binds to the alpha(2)-adrenergic receptor. The present results are consistent with a direct connection between periodontitis and stress, and describe a novel mechanism that may contribute to pathological platelet activation.

  • 7.
    Osman, Abdimajid
    et al.
    Clinical and Experimental Medicine, Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Fälker, Knut
    Clinical and Experimental Medicine, Department of Clinical Chemistry, Linköping University, Linköping, Sweden.
    Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 6, p. 433-41Article in journal (Refereed)
    Abstract [en]

    Platelets are anucleate blood cells that play a crucial role in thrombosis and hemostasis. Despite their lack of nuclear DNA, platelets contain significant amounts of microRNA (miRNA) that may have vital functions in post-transcriptional gene regulation. Here, we combined comprehensive miRNA expression profiling by quantitative PCR with target prediction analysis for the most abundant miRNAs in human platelets. A network composed of predicted platelet miRNA target genes was then constructed, using annotations available in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. In addition, we evaluated possible differences in miRNA levels between resting and thrombin-stimulated platelets. We identified 281 transcripts, including 228 mature miRNAs and 53 minor miRNAs (or miR*), of which six miRNAs (miR-15 a, miR-339-3 p, miR-365, miR-495, miR-98, and miR-361-3 p) were up- or down-regulated in activated human platelets (P ≤ 0.001). A redundancy-reduced network was established that encompassed 246 genes in five statistically significant functional clusters representing platelet miRNA regulating pathways. Comparison of the 246 network genes with the platelet mRNA expression data available at ArrayExpress database confirmed that most of these genes (89%) are expressed in human platelets. In conclusion, this work affirms a recent microarray study reporting a wide-spread existence of miRNAs in human platelets. Further, we observed that thrombin stimulation was associated with altered levels of some miRNAs in platelets. The proposed functional network, combining computational prediction analysis with annotations from experimental observations, may in addition provide some information about probable miRNA target pathways in human platelets.

  • 8.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Arachidonic acid causes lysis of blood cells and ADP-dependent platelet activation responses in platelet function tests2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635Article in journal (Refereed)
    Abstract [en]

    The use of arachidonic acid (AA) to stimulate platelets is considered as a specific approach to study aspirin treatment efficacy. However, very high concentrations of AA are used, and it has been previously reported that AA can induce cell lysis in other settings. Several clinical studies have reported decreased responses to AA in whole blood tests in the presence of clopidogrel. Our aim was to investigate whether unspecific effects contribute to AA-induced aggregation and platelet activation in light transmission aggregometry (LTA) in platelet-rich plasma (PRP), and in assays using whole blood, multiple electrode aggregometry (MEA, Multiplate®), and flow cytometry. We report that cell lysis, especially of red blood cells, does occur at concentrations of AA used in the clinical tests and that ADP is very important for the AA-induced platelet activation responses. In flow cytometry, very limited platelet activation was detected before reaching AA concentrations in the millimolar range, where cell lysis also occurred, making it problematic to develop a reliable flow cytometry assay using AA as reagent. We conclude that cell lysis and ADP release contribute to AA-induced platelet responses, most markedly in whole blood assays. This finding could potentially explain some differences between studies comparing methods using whole blood and PRP and also how clopidogrel treatment could influence AA-induced aggregation results in previously published studies. Our findings highlight some issues with AA as reagent for platelet activation, which also have an impact on how platelet activation assays using AA should be interpreted.

  • 9.
    Ramström, Sofia
    et al.
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    O'Neill, Sarah
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Dunne, Eimear
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Kenny, Dermot
    Biomedical Diagnostics Institute (BDI) Programme, Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland.
    Annexin V binding to platelets is agonist, time and temperature dependent2010In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 21, no 4, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Platelets bind annexin V when stimulated with combinations of platelet agonists such as collagen and thrombin. Previous studies have demonstrated significant heterogeneity of platelets binding annexin V. The relative role of the thrombin protease-activated receptors (PARs), PAR1 and PAR4, together with different methods of platelet preparation on annexin V binding to platelets is unclear. We therefore investigated the role of PAR1- and PAR4-activating peptides in combination with collagen-related peptide on annexin V binding. In diluted whole blood, PAR1- and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding. However, in washed platelets, PAR-activating peptides were less potent than thrombin at inducing annexin V binding. This difference was more pronounced when experiments were performed at 37 degrees C compared to room temperature. In studies of diluted whole blood, platelet rich plasma and washed platelets, platelets incubated at room temperature bound more annexin V than platelets incubated at 37 degrees C. We also saw a significant effect of time on annexin V binding, in that more annexin V bound to platelets with longer incubation times. In conclusion, PAR1 and PAR4-activating peptides were as effective as thrombin in inducing annexin V binding in combination with collagen-related peptide in diluted whole blood and platelet rich plasma, but not in washed platelets. In addition, incubation temperature and time has a strong influence on annexin V binding to platelets. Thus variations in these conditions may explain the differences observed between previous studies.

  • 10.
    Sodergren, Anna L.
    et al.
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Holm, Ann-Charlotte B. Svensson
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Lindström, Eva G.
    Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Department of Medical and Health Sciences, Faculty of Health Sciences, Linkoöping University, Linköping, Sweden; Department of Clinical Medicine, Örebro University Hospital, Örebro, Sweden.
    Öllinger, Karin
    Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Thrombin-induced lysosomal exocytosis in human platelets is dependent on secondary activation by ADP and regulated by endothelial-derived substances2016In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 27, no 1, p. 86-92Article in journal (Refereed)
    Abstract [en]

    Exocytosis of lysosomal contents from platelets has been speculated to participate in clearance of thrombi and vessel wall remodelling. The mechanisms that regulate lysosomal exocytosis in platelets are, however, still unclear. The aim of this study was to identify the pathways underlying platelet lysosomal secretion and elucidate how this process is controlled by platelet inhibitors. We found that high concentrations of thrombin induced partial lysosomal exocytosis as assessed by analysis of the activity of released N-acetyl--glucosaminidase (NAG) and by identifying the fraction of platelets exposing the lysosomal-associated membrane protein (LAMP)-1 on the cell surface by flow cytometry. Stimulation of thrombin receptors PAR1 or PAR4 with specific peptides was equally effective in inducing LAMP-1 surface expression. Notably, lysosomal exocytosis in response to thrombin was significantly reduced if the secondary activation by ADP was inhibited by the P2Y(12) antagonist cangrelor, while inhibition of thromboxane A(2) formation by treatment with acetylsalicylic acid was of minor importance in this regard. Moreover, the NO-releasing drug S-nitroso-N-acetyl penicillamine (SNAP) or the cyclic AMP-elevating eicosanoid prostaglandin I-2 (PGI(2)) significantly suppressed lysosomal exocytosis. We conclude that platelet inhibitors that mimic functional endothelium such as PGI(2) or NO efficiently counteract lysosomal exocytosis. Furthermore, we suggest that secondary release of ADP and concomitant signaling via PAR1/4- and P2Y(12) receptors is important for efficient platelet lysosomal exocytosis by thrombin.

  • 11. Svensson Holm, A.-C.
    et al.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences.
    Grenegård, M.
    Lindström, E. G.
    Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species2008In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 19, no 7, p. 528-536Article in journal (Refereed)
    Abstract [en]

    Continuous recruitment and inappropriate activity of platelets in the airways may contribute to airway remodeling, a characteristic feature of inflammatory airway diseases that includes increased proliferation of the smooth muscle. The aim of the present investigation was to examine the effect of platelets on proliferation of airway smooth muscle cells (ASMC) in culture and to determine the possible role of 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) in this context. ASMC obtained from guinea pigs were cultured and co-incubated with washed platelets for 24 hours. Thereafter, the proliferation was measured with the MTS-assay; the results were also verified by using thymidine incorporation, DNA measurements and manual counting. The interaction between platelets and ASMC was visualized with fluorescence microscopy. We found that platelets bind to the ASMC and the presence of platelets caused a significant dose-dependent increase in ASMC proliferation. Co-incubation of ASMC with platelets also increased ROS-production, detected by the fluorescent probe DCFDA. Furthermore, the platelet-induced proliferation was reduced in the presence of the NADPH-oxidase inhibitors DPI and apocynin. A possible role of 5-LOX in platelet-induced proliferation and ROS-generation was evaluated by using the 5-LOX inhibitor AA-861 and the PLA2-inhibitor ATK. The results showed that inhibition of these enzymes significantly reduced the platelet-induced proliferation. Moreover, Western blot analysis revealed that the ASMC but not the platelets express 5-LOX. In addition, our experiments revealed that the presence of AA-861 and ATK significantly inhibited the ROS-production generated upon co-incubation of platelets and ASMC. In conclusion, we show that platelets have a marked capacity to induce ASMC proliferation. Furthermore, our study indicates that the interaction between platelets and ASMC leads to activation of 5-LOX in the ASMC followed by an increased ROS-production, events resulting in enhanced ASMC proliferation. The new findings are of importance in understanding possible mechanisms contributing to airway remodeling. © 2008 Informa UK Ltd.

  • 12. Svensson Holm, Ann-Charlotte B.
    et al.
    Bengtsson, Torbjörn
    Örebro University, School of Health and Medical Sciences.
    Grenegard, Magnus
    Lindström, Eva G.
    Platelet membranes induce airway smooth muscle cell proliferation2011In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, no 1, p. 45-55Article in journal (Refereed)
    Abstract [en]

    The role of platelets in airway disease is poorly understood although they have been suggested to influence on proliferation of airway smooth muscle cells (ASMC). Platelets have been found localized in the airways in autopsy material from asthmatic patients and have been implicated in airway remodeling. The aim of the present study was to investigate the effects of various platelet fractions on proliferation of ASMC obtained from guinea pigs (GP-ASMC) and humans (H-ASMC). Proliferation of ASMC was measured by the MTS assay and the results confirmed by measurements of the DNA content. A key observation was that the platelet membrane preparations induced a significant increase in the proliferation of both GP-ASMC (129.9 +/- 3.0 %) and H-ASMC (144.8 +/- 12.2). However, neither supernatants from lysed or filtrated thrombin stimulated platelets induced ASMC proliferation to the same extent as the membrane preparation. We have previously shown that platelet-induced proliferation is dependent on 5-lipoxygenase (5-LOX) and reactive oxygen species (ROS) pathways. In the present work we established that platelet membrane-induced ASMC proliferation was reduced in the presence of the NADPH oxidase inhibitor DPI and the 5-LOX inhibitor AA-861. In conclusion, our results showed that platelet membranes significantly induced ASMC proliferation, demonstrating that the mitogenic effect of platelets and platelet membranes on ASMC is mainly due to membrane-associated factors. The effects of platelet membranes were evident on both GP-ASMC and H-ASMC and involved 5-LOX and ROS. These new findings are of importance in understanding the mechanisms contributing to airway remodeling and may contribute to the development of new pharmacological tools in the treatment of inflammatory airway diseases.

  • 13.
    Tynngård, Nahreen
    et al.
    Department of Clinical and Experimental Medicine, Division of Transfusion Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Immunology and Transfusion Medicine, County Council of Östergötland, Linköping, Sweden; Department of Clinical Chemistry, County Council of Östergötland, Linköping, Sweden.
    Wallstedt, Maria
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Södergren, Anna L.
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Fac Hlth Sci, Dept Clin & Expt Med, Div Clin Chem, Linkoping Univ, Linkoping, Sweden..
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Division of Clinical Chemistry, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Clinical Chemistry, County Council of Östergötland, Linköping, Sweden.
    Platelet adhesion changes during storage studied with a novel method using flow cytometry and protein-coated beads2015In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 26, no 2, p. 177-185Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to set up and evaluate a novel method for studies of platelet adhesion and activation in blood and platelet suspensions such as platelet concentrate (PC) samples using protein-coated polystyrene beads and flow cytometry. To demonstrate its usefulness, we studied PCs during storage. PCs were prepared by aphaeresis technique (n = 7). Metabolic variables and platelet function was measured on day 1, 5, 7 and 12 of storage. Spontaneous and TRAP-6-induced adhesion to fibrinogen-and collagen-coated beads was analyzed by flow cytometry. P-selectin and phosphatidyl serine (PS) expression was assessed on platelets bound to beads as well as on non-adherent platelets. Platelet adhesion to fibrinogen beads had increased by day 12 and adhesion to collagen beads at day 7 of storage (p<0.05). TRAP-6 stimulation significantly increased the platelet adhesion to fibrinogen beads (p<0.05) as well as the P-selectin and PS exposure on platelets bound to beads (p<0.01) during the first 7 days of storage, but by day 12, significant changes were no longer induced by TRAP-6 stimulation. We demonstrate that our adhesion assay using protein-coated polystyrene beads can be used to assess the adhesion properties of platelets during storage without the addition of red blood cells. Therefore it may offer a useful tool for future studies of platelet adhesive capacity in transfusion medicine and other settings.

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