Mairi Brittan

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (57)379.62 Total impact


  • No preview · Conference Paper · Nov 2015
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    ABSTRACT: Endothelial dysfunction is central to the pathogenesis of coronary artery disease, but the role of local and circulating endothelial progenitor cells in maintaining vascular health is poorly understood. We hypothesised that impaired local and circulating vascular repair mechanisms predispose to endothelial dysfunction and the premature onset of coronary artery disease. Patients with premature coronary artery disease (n = 16) and healthy age- and sex-matched controls (n = 16) underwent venous occlusion plethysmography with intra-arterial infusion of acetylcholine and sodium nitroprusside. Numbers of circulating endothelial progenitor cells were directly quantified in whole blood by flow cytometry. Endothelial cells were isolated from the blood vessel wall and from peripheral blood mononuclear cells, and expanded in vitro for phenotypic and functional characterisation and analysis of microRNA expression levels. A dose-dependent increase in forearm blood flow (p < 0.001) was attenuated in response to the endothelial-dependent vasodilator acetylcholine in patients compared with controls (p = 0.03). No differences in the number of circulating endothelial progenitor cells or in the phenotype, function or microRNA expression levels of endothelial outgrowth cells isolated from blood were observed in patients and controls. Conversely, local vessel wall endothelial cells from patients had significant impairments in proliferation, adhesion and migration, and significantly reduced expression levels of microRNAs known to regulate endothelial function (miRs -10 a, -let7b, -126 and -181 b) (p < 0.05 for all). Local vessel wall derived endothelial cells, rather than circulating endothelial progenitor cells and their progeny, are impaired in patients with vascular dysfunction and premature coronary artery disease. © The European Society of Cardiology 2015.
    No preview · Article · Aug 2015

  • No preview · Article · Jul 2015 · Atherosclerosis

  • No preview · Article · Jul 2015 · Atherosclerosis

  • No preview · Article · Jul 2015 · Atherosclerosis

  • No preview · Article · Jul 2015 · Atherosclerosis
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    ABSTRACT: Turnover of the epithelial cell lineages within the gastrointestinal tract is a constant process, occurring every two to seven days under normal homeostasis and at increased rates after damage. This process is regulated by multipotent stem cells, which generate all gastrointestinal epithelial cell lineages and can regenerate whole intestinal crypts and gastric glands. The stem cells of the gastrointestinal tract are as yet undefined, although it is generally agreed that they are located within a 'niche' in the intestinal crypts and gastric glands. Studies of allophenic, tetraparental chimeric mice and targeted stem cell mutations suggest that a single stem cell undergoes an asymmetrical division to produce an identical daughter cell, thus replicating itself, and a committed progenitor cell, which further differentiates into an adult epithelial cell type. The discovery of stem cell plasticity in many tissues, including the ability of transplanted bone marrow to transdifferentiate into intestinal subepithelial myofibroblasts, provides a potential use of bone marrow cells to deliver therapeutic genes to damaged tissues, for example, in the treatment of mesenchymal diseases in the gastrointestinal tract, such as fibrosis and Crohn's disease. Studies are beginning to identify the molecular pathways that regulate stem cell proliferation and differentiation into adult gastrointestinal cell lineages, such as the Wnt and Notch-Delta signaling pathways, and to discover the importance of mesenchymal-epithelial interactions in normal gastrointestinal epithelium and in development and disease. Finally, despite some dispute, a strong case can be made for intestinal neoplasia arising as a result of a series of mutations in stem cells. The mechanism and direction of the spread of this mutated clone in the gastrointestinal mucosa is hotly disputed, and central to this argument is the position and nature of the gastrointestinal stem cell.
    No preview · Chapter · Dec 2014
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    ABSTRACT: The observation that pathogenic bacteria are commonly tolerated in the human nose, yet drive florid inflammation in the lung, is poorly understood, partly due to limited availability of primary human cells from each location. We compared responses to bacterial virulence factors in primary human nasal and alveolar cells, and characterised the distribution of Toll-interacting protein (TOLLIP; an inhibitor of Toll-like receptor (TLR) signalling) in the human respiratory tract. Primary cells were isolated from nasal brushings and lung tissue taken from patients undergoing pulmonary resection. Cells were exposed to lipopolysaccharide, lipoteichoic acid, peptidoglycan, CpG-C DNA or tumour necrosis factor (TNF). Cytokines were measured in cell supernatants. TOLLIP was characterised using quantitative real-time PCR and immunofluorescence. In primary alveolar, but not primary nasal, cells peptidoglycan significantly increased secretion of interleukin (IL)-1β, IL-6, IL-8, IL-10 and TNF. TLR2 expression was significantly higher in alveolar cells and correlated with IL-8 production. TOLLIP expression was significantly greater in nasal cells. In conclusion, primary human alveolar epithelial cells are significantly more responsive to peptidoglycan than primary nasal epithelial cells. This may partly be explained by differential TLR2 expression. TOLLIP is expressed widely in the human respiratory tract, and may contribute to the regulation of inflammatory responses.
    Full-text · Article · May 2014
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    ABSTRACT: The primary aim of this prospective study was to perform a comprehensive serial characterisation of monocyte and neutrophil function, circulating monocyte subsets, and bronchoalveolar lavage (BAL) fluid after lung resection. A secondary aim was to perform a pilot, hypothesis-generating evaluation of whether innate immune parameters were associated with postoperative pneumonia. Forty patients undergoing lung resection were studied in detail. Blood monocytes and neutrophils were isolated preoperatively and at 6, 24 and 48 h postoperatively. BAL was performed preoperatively and immediately postoperatively. Monocyte subsets, monocyte responsiveness to lipopolysaccharide (LPS) and neutrophil phagocytic capacity were quantified at all time points. Differential cell count, protein and cytokine concentrations were measured in BAL. Pneumonia evaluation at 72 h was assessed using predefined criteria. After surgery, circulating subsets of classical and intermediate monocytes increased significantly. LPS-induced release of proinflammatory cytokines from monocytes increased significantly and by 48 h a more proinflammatory profile was found. Neutrophil phagocytosis demonstrated a small but significant fall. Factors associated with postoperative pneumonia were: increased release of specific proinflammatory and anti-inflammatory cytokines from monocytes; preoperative neutrophilia; and preoperative BAL cell count. We conclude that postoperative lung inflammation is associated with specific changes in the cellular innate immune response, a better understanding of which may improve patient selection and prediction of complications in the future.
    Full-text · Article · May 2014
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    ABSTRACT: Innate immune responses to pulmonary resection may be critical in the pathogenesis of important postoperative pulmonary complications and potentially longer-term survival. We sought to compare innate immunity of patients undergoing major pulmonary resection for bronchogenic carcinoma via video-assisted thoracoscopic surgery (VATS) and thoracotomy. Bronchoalveolar lavage was conducted in the contralateral lung before staging bronchoscopy and mediastinoscopy and immediately after lung resection. Blood and exhaled nitric oxide were sampled preoperatively and at 6, 24, and 48 hours postoperatively. Forty patients were included (26 VATS and 14 thoracotomy). There was a lower systemic cytokine response from lung resection undertaken by VATS compared with thoracotomy [interleukin 6 (IL-6), analysis of variance (ANOVA) P = 0.026; IL-8, ANOVA P = 0.018; and IL-10, ANOVA P = 0.047]. The VATS patients had higher perioperative serum albumin levels (ANOVA P = 0.001). Lower levels of IL-10 were produced by lipopolysaccharide-stimulated blood monocytes from the VATS patients compared with the thoracotomy patients at 6 hours postoperatively (geometric mean ratio, 1.16; 95% confidence interval, 1.08-1.33; P = 0.011). No statistically significant differences in the neutrophil phagocytic capacity, overall leukocyte count, or differential leukocyte count were found between the surgical groups (ANOVA P > 0.05). No statistically significant differences in bronchoalveolar lavage fluid parameters were found. Exhaled nitric oxide levels fell postoperatively, which reached statistical significance at 48 hours (geometric mean ratio, 1.2; 95% confidence interval, 1.02-1.46; P = 0.029). There were no significant differences found between the surgical groups (ANOVA P = 0.331). Overall, a trend toward greater proinflammatory and anti-inflammatory responses is seen with lung resection performed via thoracotomy compared with VATS.
    No preview · Article · Apr 2014 · Innovations Technology and Techniques in Cardiothoracic and Vascular Surgery
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    ABSTRACT: We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR+CD14++CD16+cells) and inducible PMLC (iPMLC, HLA-DR+CD14++CD16- cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We have carried out the first functional evaluation of PMLC subpopulations in the inflamed lung, following the isolation of these cells, and other lineages, from BAL fluid using novel and complex protocols. iPMLC, rPMLC, alveolar macrophages (AM), neutrophils, and regulatory T cells were quantified in BAL fluid of healthy subjects at 9 hours post-LPS inhalation (n = 15). Cell surface antigen expression by iPMLC, rPMLC and AM and the ability of each lineage to proliferate and to undergo phagocytosis were investigated using flow cytometry. Basal cytokine production by iPMLC compared to AM following their isolation from BAL fluid and the responsiveness of both cell types following in vitro treatment with the synthetic corticosteroid dexamethasone were assessed. rPMLC have a significantly increased expression of mature macrophage markers and of the proliferation antigen Ki67, compared to iPMLC. Our cytokine data revealed a pro-inflammatory, corticosteroid-resistant phenotype of iPMLC in this model. These data emphasise the presence of functionally distinct subpopulations of the monocyte/macrophage lineage in the human lung in experimental acute lung inflammation.
    Full-text · Article · Mar 2014 · Journal of Inflammation
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    Full-text · Article · Feb 2014 · American Journal of Respiratory and Critical Care Medicine
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    ABSTRACT: Rationale: The pathogenesis of chronic obstructive pulmonary disease is not fully understood. Objectives: To compare circulating endothelial progenitor cells in patients with chronic obstructive pulmonary disease to age, gender and cigarette smoking matched healthy controls. Methods and Measurements: Patients with chronic obstructive pulmonary disease (n=37) and healthy controls (n=19) were matched by age, gender and smoking status. Circulating hematopoietic progenitor cells (CD34+ or CD133+ mononuclear cells) and endothelial progenitor cells (CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) mononuclear cells) were quantified by flow cytometry. Endothelial cell-colony forming units from peripheral blood mononuclear cells were quantified in vitro and phenotypic analysis carried out using immunocytochemistry. Main Results: Patients with chronic obstructive pulmonary disease had more circulating mononuclear cells compared to controls (8.4±0.6 versus 5.9±0.4 x109 cells/L; P=0.02). CD34(+) hematopoietic progenitor cells were reduced as a proportion of mononuclear cells in patients compared to controls (0.99±0.12 versus 1.9±0.12%; P=0.02), however there were no differences in the absolute number of CD34+, CD34(+)KDR(+) or CD34(+)CD133(+)KDR(+) cells (P>0.05 for all). Endothelial cell-colony forming units were increased in patients with chronic obstructive pulmonary disease compared to controls (13.7±5.2 versus 2.7±0.9 colonies; P=0.048). Conclusions: In contrast to previous studies the number of circulating progenitor cells were not reduced in patients with chronic obstructive pulmonary disease compared with carefully matched controls. It seems unlikely that circulating endothelial progenitor cells or failure of angiogenesis play a central role in the development of emphysema.
    Full-text · Article · Oct 2013 · AJP Lung Cellular and Molecular Physiology
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    ABSTRACT: GCs are highly effective in treating a wide range of inflammatory diseases but are limited in their ability to control neutrophilic lung inflammation in conditions such as COPD. Neutrophil apoptosis, a central feature of inflammation resolution, is delayed in response to microenvironmental cues, such as hypoxia and inflammatory cytokines, present at inflamed sites. GCs delay neutrophil apoptosis in vitro, and this may therefore limit the ability of GCs to control neutrophilic inflammation. This study assesses the effect GCs have on hypoxia- and inflammatory cytokine-induced neutrophil survival. Human neutrophils were treated with GCs in the presence or absence of GM-CSF or inflammatory macrophage-CM at a range of oxygen concentrations (21-1% oxygen). Neutrophil apoptosis and survival were assessed by flow cytometry and morphological analysis and neutrophil function, by stimulus-induced shape change and respiratory burst. Dexamethasone promoted neutrophil survival at 21%, 10%, and 5% oxygen but not at 1% oxygen. Interestingly, GM-CSF and inflammatory CM increased neutrophil survival significantly, even at 1% oxygen, with cells remaining functionally active at 96 h. Dexamethasone was able to reduce the prosurvival effect of GM-CSF and inflammatory CM in a hypoxic environment. In conclusion, we found that GCs do not augment neutrophil survival in the presence of severe hypoxia or proinflammatory mediators. This suggests that GCs would not promote neutrophil survival at sites of inflammation under these conditions.
    Full-text · Article · Aug 2013 · Journal of leukocyte biology
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    M. Brittan · S. Gallogly · N. L. Mills
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    ABSTRACT: Purpose: Our understanding of endothelial cell biology is primarily derived from studies of human umbilical vein endothelial cells (HUVECs). However, HUVECs provide limited insight into disease pathogenesis. We describe a novel method for isolation of coronary artery endothelial cells from thrombectomy specimens obtained during the treatment of patients with acute myocardial infarction. We have expanded and characterised human coronary endothelial outgrowth (CEO) cells compared to HUVECs, to investigate their potential as a model of endothelial dysfunction. Methods: Patients presenting to the Edinburgh Royal Infirmary with ST-segment elevation myocardial infarction (n=15) underwent emergency percutaneous coronary intervention and thrombus aspiration. Thrombus specimens were dissected, plated onto collagen-I coated plates and maintained in vitro to encourage cellular outgrowth. Population doubling time was evaluated and angiogenic potential assessed by tubule formation. Multiparameter flow cytometry using antibodies to endothelial cell markers was performed (CD31, KDR, CD146 and CD34) and cells were immunostained for vonWillenbrand factor (vWF). Results: CEO cell outgrowth was observed in 9/15 samples. Population doubling times of CEO cells were comparable to HUVECs (mean±SD: CEO 2.6±0.5, HUVEC 2.3±0.1 days; p=0.50 student's t-test). CEO cells had typical "cobblestone" morphology and were immunoreactive for vWF. Surface expression of CD31 and KDR was comparable in both cell types (CD31 mean±SD: CEO 74.9±21.3 vs. HUVEC 89.3±11.4, p=0.13; KDR mean±SD: CEO 46.7±31.7 vs. HUVEC 22.2±15.9, p=0.11), however CD146 and CD34 expression was increased in CEO cells (CD146 mean±SD: CEO 96±5.3 vs. HUVEC 73.5±30.7, p<0.05; CD34 mean±SD: CEO 80.9±16.92 vs. HUVEC 40.63±18.06, p<0.001). Only 44% of CEO cells were capable of tubule formation compared to 100% of HUVECs (p=0.01, contingency tables, fishers exact test). CEO cells that were capable of tubule formation had reduced capacity to form connections compared to HUVECs (mean±SD: CEO 12±8, versus HUVEC 63±16 connections; p<0.0001). Conclusions: Viable coronary arterial endothelial cells can be isolated from thrombus extracted during emergency percutaneous coronary intervention. These cells have a mature endothelial phenotype comparable to HUVECs, but have reduced angiogenic potential suggesting they retain the functional characteristics of in situ endothelium. This novel approach to isolate dysfunctional endothelial cells may have applications in studies of the cellular and molecular basis of endothelial dysfunction in patients with coronary artery disease.
    Preview · Article · Aug 2013 · European Heart Journal
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    Full-text · Dataset · Jun 2013
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    ABSTRACT: Background: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. Methods: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. Results: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). Conclusions: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.
    Full-text · Article · Jun 2013 · BJA British Journal of Anaesthesia

  • No preview · Article · May 2013 · Heart (British Cardiac Society)
  • S. Gallogly · M. Brittan · O. Tura · E. Skinner · N. L. Mills

    No preview · Article · May 2013 · Heart (British Cardiac Society)
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    ABSTRACT: Rationale: Depletion of monocytes reduces lipopolysaccharide-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. Objectives: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. Methods: Thirty healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled lipopolysaccharide at baseline and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage was performed at 9 hours, and [18F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary end-point was the increment in circulating neutrophils at 8 hours. Measurements and Main Results: As expected, inhalation of lipopolysaccharide induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 x109/L and 6.15 x109/L respectively, P=1.00). Furthermore, there were no significant differences in bronchoalveolar lavage neutrophils or protein, positron emission tomography-derived measures of global lung inflammation or cytokine levels in plasma or bronchoalveolar lavage supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. Conclusions: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during lipopolysaccharide-mediated acute lung inflammation in humans.
    No preview · Article · Apr 2013 · American Journal of Respiratory and Critical Care Medicine

Publication Stats

2k Citations
379.62 Total Impact Points

Institutions

  • 2010-2015
    • The University of Edinburgh
      • • MRC Centre for Regenerative Medicine
      • • MRC Centre for Inflammation Research
      Edinburgh, Scotland, United Kingdom
  • 2006-2009
    • Queen Mary, University of London
      • • Barts and The London School of Medicine and Dentistry
      • • The Blizard Institute of Cell and Molecular Science
      Londinium, England, United Kingdom
  • 2005
    • University of Southampton
      Southampton, England, United Kingdom
  • 2002-2005
    • Cancer Research UK
      Londinium, England, United Kingdom