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1.
Haematologica ; 105(5): 1248-1261, 2020 05.
Article in English | MEDLINE | ID: mdl-31467123

ABSTRACT

Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a range of agonists in whole blood, they shed platelet-derived extracellular vesicles which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to monocytes. GPIbα+-monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-ß1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood in vitro and in vivo Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα+-monocytes adhered to the microcirculation of the TGF-ß1-stimulated cremaster muscle, while in the ApoE-/- model of atherosclerosis, GPIbα+-monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicles transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic.


Subject(s)
Blood Platelets , Extracellular Vesicles , Animals , Endothelial Cells , Humans , Inflammation , Mice , Monocytes , Platelet Glycoprotein GPIb-IX Complex
2.
Clin Hemorheol Microcirc ; 72(1): 1-10, 2019.
Article in English | MEDLINE | ID: mdl-30452405

ABSTRACT

BACKGROUND: Exposure to air pollution is associated with cardiovascular disease, including increased morbidity and mortality rates. OBJECTIVE: The aim of this investigation was to assess the effect, in rats, of intratracheal instillation of particulate air pollution on biomarkers of leucocyte activation and vascular endothelial damage. METHODS: Air pollution particles (PM10) were instilled into rats, and blood samples were taken three days and six weeks post instillation. Plasma neutrophil elastase and Von Willebrand factor were measured by ELISA. RESULTS: Plasma neutrophil elastase increased from 175±44 ng/ml at baseline to 288±26 ng/ml 3 days post instillation (p = 0.038). vWF increased from 0.160±0.015 IU/ml at baseline to 0.224±0.015 IU/ml at 3 days post and 0.208±0.01 IU/ml at 6 weeks post (p = 0.006, ANOVA). sICAM-1 increased from 17.75±0.70 ng/ml at baseline to 19.03±0.33 ng/ml at 3 days post and 21.72±1.16 ng/ml at 6 weeks post (p = 0.009, ANOVA). CONCLUSION: Instillation caused prolonged systemic inflammation, activation of blood leucocytes and damage to the vascular endothelium.


Subject(s)
Air Pollution/analysis , Endothelium, Vascular/physiopathology , Inflammation/etiology , Nanoparticles/metabolism , Animals , Cardiovascular Diseases , Male , Rats , Rats, Sprague-Dawley
3.
Clin Hemorheol Microcirc ; 59(4): 365-77, 2015.
Article in English | MEDLINE | ID: mdl-25000923

ABSTRACT

Hypertension, decreased glucose tolerance, adverse lipid profiles and low physical activity levels are associated with increased type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) risk. High intensity interval training (HIIT), a low volume, reduced time, high intensity programme, may be a useful alternative to current government guidelines which specify a minimum of 150 minutes of physical activity per week. We describe a personalised programme of high intensity exercise which provides significant improvements in CVD risk markers. Healthy volunteers undertook 6 weeks of HIIT. T2DM and CVD risk predictors including glucose tolerance, VO2max, blood pressure (BP), and lipids were measured before and after HIIT. HIIT training was associated with beneficial changes in a range of predictors of blood flow and cardiovascular risk. There was a heterogeneous response to HIIT, with some subjects responding with favourable changes and others being non-responders to HIIT. In responders, HIIT was associated with a statistically significant (p = 0.023) increase in VO2max, from 45.4 (38.4,52.5) to 56.9 (51.2,65.7) (median (interquartile range)(ml/min/kg)). In responders HIIT resulted in a decrease in systolic BP from 127 (126,129) to 116 (106,122) (mmHg) with p = 0.026 and a decrease is diastolic blood pressure from 72 (69,74) to 57 (56,66) with p = 0.026. There was also some evidence of a beneficial change in blood lipid and glucose concentrations with HIIT. In conclusion, personalised HIIT has potential as an intervention to improve blood flow and cardiovascular health.


Subject(s)
Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Exercise Therapy/methods , Cardiovascular Diseases/therapy , Diabetes Mellitus, Type 2/therapy , Healthy Volunteers , Humans , Risk Factors , Treatment Outcome
4.
Biorheology ; 51(4-5): 329-38, 2014.
Article in English | MEDLINE | ID: mdl-25313190

ABSTRACT

BACKGROUND: Exposure to particulate air pollution is associated with an increased risk of cardiovascular disease. The mechanism by which exposure increases risk is poorly understood but could involve changes in the flow properties of blood. OBJECTIVE: The aim of this investigation was to assess the effect, in rats, of intratracheal instillation of particulate air pollution on leukocyte flow properties by measurement of polymorphonucleocyte (PMN) and monocyte actin polymerisation. METHODS: Rats were exposed to particulate air pollution by intratracheal instillation of PM10. Blood was collected from test and control animals at 3 days (n=10) and 6 weeks (n=10) after dust instillation. Partial differential leukocyte counts were performed. The intracellular F-actin content of blood PMNs and monocytes was determined by staining with FITC-phalloidin and flow cytometric determination of mean florescence intensity (MFI). RESULTS: There were no significant changes in PMN MFI (p=0.369, ANOVA) or cell counts (p=0.753, ANOVA). There was a significant increase in monocyte MFI (p=0.004, ANOVA) and a decrease in monocyte cell count (p=0.003, ANOVA) in instilled rats. CONCLUSIONS: Intratracheal instillation of air pollution particles resulted in an increase in blood monocyte actin polymerisation, which may cause trapping of monocytes. This could be a mechanism by which exposure to air pollution increases the risk of cardiovascular disease.


Subject(s)
Actins/metabolism , Monocytes/cytology , Particulate Matter/chemistry , Trachea/pathology , Animals , Cardiovascular System/drug effects , Cytoskeleton/metabolism , Flow Cytometry , Hemorheology/physiology , Inflammation , Leukocytes/cytology , Male , Monocytes/drug effects , Neutrophils/cytology , Particle Size , Polymerization , Rats , Rats, Sprague-Dawley , Trachea/drug effects
5.
Clin Hemorheol Microcirc ; 52(1): 57-65, 2012.
Article in English | MEDLINE | ID: mdl-22796755

ABSTRACT

Cardiovascular disease is a major cause of morbidity and mortality in the developed world. Large epidemiological studies have reported a strong association between increases in haematological factors and increased cardiovascular risk. Haematological risk factors predicted cardiovascular disease at least as strongly as traditional risk factors such as blood lipid concentrations. Lifestyle factors such as physical activity level could significantly reduce risk. The aim of this study was to determine the effect of physical activity level on haematological predictors of cardiovascular risk. Healthy subjects (156) were recruited. Physical activity in subjects was assessed by IPAQ physical activity questionnaire. Blood was collected and blood cell counts were determined by automated cell counter; neutrophil elastase was determined by ELISA. Increased levels of physical activity were associated with reduced red cell (p = 0.001), white cell (p = 0.002) and platelet counts (p = 0.001) and with reduced plasma neutrophil elastase concentration (p = 0.001). There was a continuous linear relationship between increase in physical activity and decrease in haematological risk factors. Hence, the authors conclude that increased levels of physical activity improve the flow properties of blood and thus reduce the risk of developing cardiovascular disease. Even small increases in activity result in some reduction in cardiovascular risk.


Subject(s)
Cardiovascular Diseases/blood , Cardiovascular Diseases/epidemiology , Blood Cell Count , Cardiovascular Diseases/diagnosis , Exercise , Hemorheology , Humans , Leukocyte Elastase/blood , Life Style , Risk Factors , Surveys and Questionnaires
6.
Exp Lung Res ; 32(8): 363-78, 2006 Sep.
Article in English | MEDLINE | ID: mdl-17090477

ABSTRACT

Increased exposure to pollution has been implicated in cardiovascular malfunction, and although studies show a relationship between PM10 and mortality, the exact biological causes are unclear. This study investigated how compromised lungs respond to instillation of nanoparticles, and the links between exposure to nanoparticles and the subsequent effects on the blood. Instillation of diesel exhaust particles and Cabosil caused significant permeability and inflammatory changes in both bleomycin-treated and control lungs, as shown by increased lung surface protein and lung:body weight ratio. This was true in edematous and maximally repairing lungs, but without significant hematological alterations. Plasma viscosity, a renowned marker for cardiovascular disease, correlated strongly statistically with free cell numbers, type I cell marker rT140, and lung acellular protein. These correlations are a new and novel insight into the mechanisms linking air pollution to cardiovascular mortality.


Subject(s)
Air Pollutants/toxicity , Cardiovascular Diseases/chemically induced , Nanoparticles/toxicity , Pneumonia/chemically induced , Vehicle Emissions/toxicity , Animals , Antibiotics, Antineoplastic , Bleomycin , Blood Viscosity/drug effects , Cardiovascular Diseases/physiopathology , Disease Models, Animal , Male , Pneumonia/pathology , Pneumonia/physiopathology , Pulmonary Edema/chemically induced , Pulmonary Edema/pathology , Pulmonary Edema/physiopathology , Rats , Rats, Sprague-Dawley , Respiratory Mucosa/drug effects , Respiratory Mucosa/pathology , Respiratory Mucosa/physiology , Silicon Dioxide
7.
Biochem Biophys Res Commun ; 333(2): 455-62, 2005 Jul 29.
Article in English | MEDLINE | ID: mdl-15950942

ABSTRACT

Monocyte hyperactivation as seen in diabetes results in increased cytoskeletal rigidity and reduced cell deformability leading to microchannel occlusions and microvascular complications. The thiazolidinediones (TZDs) are PPAR-gamma agonists that have been reported to exert beneficial non-metabolic effects on the vasculature. This study demonstrates that the TZD, Rosiglitazone, significantly reduces f-MLP-induced actin polymerisation in human monocytic cells (p < 0.05). Two of the key signalling processes known to be involved in the regulation of cytoskeletal remodelling were investigated: PI(3)K-dependent Akt phosphorylation and intracellular calcium concentration [Ca(2+)](i). The PI(3)K inhibitor, Wortmannin, ameliorated f-MLP-induced actin polymerisation (p < 0.05), while the Ca(2+) sequestration inhibitor, thapsigargin, induced actin depolymerisation (p < 0.05), confirming the involvement of both processes in cytoskeletal remodelling. Rosiglitazone significantly reduced f-MLP activation of Akt (p < 0.05), and significantly increased [Ca(2+)](i) in both resting and f-MLP-stimulated cells (p < 0.05). Therefore, Rosiglitazone interacts with signalling events downstream of occupancy of the f-MLP receptor, to modulate cytoskeletal remodelling in a PPAR-gamma-independent manner. To our knowledge, these results are the first to present evidence that a PPAR-gamma agonist can modulate actin remodelling in monocytes, and may therefore be protective against microvascular damage in diabetes.


Subject(s)
Actins/metabolism , Calcium/metabolism , Leukocytes, Mononuclear/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Thiazolidinediones/administration & dosage , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Intracellular Fluid/metabolism , Leukocytes, Mononuclear/drug effects , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Proto-Oncogene Proteins c-akt , Rosiglitazone
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