A5006903396- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cell Adhesion Molecules Research
- Extracellular vesicles in disease
- Atherosclerosis and Cardiovascular Diseases
- Blood properties and coagulation
- Immune Response and Inflammation
- Angiogenesis and VEGF in Cancer
- Nitric Oxide and Endothelin Effects
- Immune cells in cancer
- Platelet Disorders and Treatments
- Congenital heart defects research
- Neuroinflammation and Neurodegeneration Mechanisms
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Chemokine receptors and signaling
- Cellular Mechanics and Interactions
- Inflammasome and immune disorders
- Protease and Inhibitor Mechanisms
- MicroRNA in disease regulation
- Barrier Structure and Function Studies
- Cardiovascular Disease and Adiposity
- Eicosanoids and Hypertension Pharmacology
- Cancer, Hypoxia, and Metabolism
- Cerebrovascular and Carotid Artery Diseases
- Erythrocyte Function and Pathophysiology
- Kruppel-like factors research
University of Sheffield
2014-2024
Royal Hallamshire Hospital
2024
Insigneo
2016-2022
Centre for Life
2019
The Wallace H. Coulter Department of Biomedical Engineering
2017
German Centre for Cardiovascular Research
2017
Georgia Institute of Technology
2017
Loughborough University
2017
Ludwig-Maximilians-Universität München
2017
University of Leeds
2016
Objective— Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites characterized by excessive endothelial cell (EC) proliferation inflammation promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible 1α) is canonically activated hypoxia has a role in plaque neovascularization. We studied the influence on activation contribution this noncanonical pathway Approach Results— Quantitative polymerase chain...
Abstract The role of alveolar macrophages (AM) in host defense against pulmonary infection has been difficult to establish using vivo models. This may reflect a reliance on models fulminant infection. To unique model resolving infection, with which address the function AM, C57BL/6 mice received low-dose intratracheal administration pneumococci. Administration low doses pneumococci produced characterized by clearance bacteria without features pneumonia. AM depletion this significantly...
Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying stress-regulation EndMT are uncertain. Here we investigated the role transcription factor Snail in low stress-induced EndMT. Studies cultured exposed to revealed that induced expression. Using gene silencing it was demonstrated...
Rationale: Blood flow–induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed embryogenesis, but its role in EC responses to and focal unknown. Objective: To investigate whether regulates vascular dysfunction compare function development disease. Methods Results: expression of TWIST1 was studied both developing vasculature the initiation...
Abstract Neutrophils are implicated in the pathogenesis of atherosclerosis but seldom detected atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels circulating neutrophil enhanced by exposure to a high fat diet, known risk factor for atherosclerosis. Neutrophil accumulate at disease-prone regions arteries exposed disturbed flow patterns, and promote vascular inflammation murine model. Using...
Rationale: Patients with chronic obstructive pulmonary disease (COPD) experience excess cardiovascular morbidity and mortality, exacerbations further increase the risk of such events. COPD is associated persistent blood airway neutrophilia systemic tissue hypoxia. Hypoxia augments neutrophil elastase release, enhancing capacity for injury. Objective: To determine whether hypoxia-driven protein secretion contributes to endothelial damage in COPD. Methods: The healthy human secretome generated...
The endothelium is critically involved in the pathogenesis of atherosclerosis by producing pro-inflammatory mediators, including IL-1β. Coronary arteries from patients with ischemic heart disease express large amounts IL-1β endothelium. However, mechanism which endothelial cells (ECs) release remains to be elucidated. We investigated neutrophil elastase (NE), a potent serine protease detected vulnerable areas human carotid plaques, as potential "trigger" for processing and release. This...
Summary Factor XIII is responsible for the cross-linking of fibrin γ-chains in early stages clot formation, whilst α-chain occurs at a slower rate. Although γ- and was previously shown to contribute stiffness, role both chains determining structure currently unknown. Therefore, aim this study determine individual α- γ-chain during its effects on structure. We made use recombinant fibrinogen (γQ398N/Q399N/K406R), which does not allow y-chain cross-linking. In absence cross-linking, intact D-D...
ABSTRACT Endothelial cell (EC) sensing of fluid shear stress direction is a critical determinant vascular health and disease. Unidirectional flow induces EC alignment homeostasis, whereas bidirectional has pathophysiological effects. ECs express several mechanoreceptors that respond to flow, but the mechanism for poorly understood. We determined, by using in vitro systems magnetic tweezers, β1 integrin key sensor force because it activated unidirectional, not bidirectional, shearing forces....
Abstract Neutrophil migration to lung alveoli is a characteristic of diseases and thought occur primarily via capillaries rather than postcapillary venules. The role adhesion molecules CD18 CD29 on this in mouse model inflammation has been investigated. number neutrophils present bronchoalveolar lavage fluid was determined 4 h after intratracheal instillation LPS (0.1–1 μg) or murine recombinant KC (CXC chemokine, 0.03–0.3 μg). Both stimuli produced dose-related increase neutrophil...
Abstract Caspase-1, the prototypic caspase, is known to process cytokines IL-1β and IL-18 mature forms but it unclear whether, like other caspases, can induce apoptosis by activation of downstream protease cascades. Neutrophils are express caspase-1, release undergo rapid, caspase-dependent apoptosis. We examined production in peripheral blood neutrophils caspase-1-deficient wild-type mice. Constitutive was delayed compared with LPS-mediated inhibition absent, were susceptible Fas-mediated...
Atherosclerosis is initiated at branches and bends of arteries exposed to disturbed blood flow that generates low shear stress. This mechanical environment promotes lesions by inducing endothelial cell (EC) apoptosis dysfunction via mechanisms are incompletely understood. Although transcriptome-based studies have identified multiple shear-responsive genes, most them an unknown function. To address this, we investigated whether zebrafish embryos can be used for functional screening...
The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement molecules between periphery and central nervous system. Elevated systemic levels neutrophils have been detected in patients with altered BBB function, but role BMEC dysfunction is unknown. Neutrophils key players immune response and, when activated, produce neutrophil-derived microvesicles (NMV). NMV shown to impact integrity...
Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays central role in vessel growth homeostasis, but its potential has not been previously studied. Here, we show using porcine murine cultured human coronary artery EC activates the JAG1-NOTCH4 signaling pathway. Light-sheet imaging revealed enrichment JAG1 NOTCH4 atherosclerotic plaques, EC-specific...
Atherosclerosis is a major cause of death globally. It characterised by the development fibro-fatty lesions in artery wall that can impede blood flow and lead to myocardial infarction. Historically, research has focused primarily on plaque rupture. However, importance erosion endothelium leading thrombosis plaques with lower lipid content, fewer inflammatory cells thick fibrous cap emerged. Neutrophils have recently been implicated through induction endothelial cell dysfunction. produce...
In the PLATO study, ticagrelor was associated with fewer pulmonary infections and subsequent deaths than clopidogrel. Neutrophils are a first-line defence against bacterial lung infection; inhibits cellular uptake of adenosine, known regulator neutrophil chemotaxis phagocytosis. We assessed whether inhibition adenosine by influences erythrocytes were isolated from healthy volunteers. Concentration-dependent effects on IL-8-induced investigated involved receptors identified using receptor...
Stent deployment causes endothelial cells (EC) denudation, which promotes in-stent restenosis and thrombosis. Thus regrowth in stented arteries is an important therapeutic goal. struts modify local hemodynamics, however the effects of flow perturbation on EC injury repair are incompletely understood. By studying stent migration, we identified intervention that arteries.In vitro vivo models were developed to monitor endothelialization under influence struts. A 2D parallel-plate chamber with...