Mairi Brittan

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (52)358.82 Total impact

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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.
    08/2015; 22(12). DOI:10.1177/2047487315600169

  • Atherosclerosis 07/2015; 241(1):e41-e42. DOI:10.1016/j.atherosclerosis.2015.04.149 · 3.99 Impact Factor

  • Atherosclerosis 07/2015; 241(1):e44. DOI:10.1016/j.atherosclerosis.2015.04.157 · 3.99 Impact Factor

  • Atherosclerosis 07/2015; 241(1):e73. DOI:10.1016/j.atherosclerosis.2015.04.254 · 3.99 Impact Factor

  • Atherosclerosis 07/2015; 241(1):e55. DOI:10.1016/j.atherosclerosis.2015.04.196 · 3.99 Impact Factor
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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.
    05/2014; 1(1):e000046. DOI:10.1136/bmjresp-2014-000046
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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.
    05/2014; 1(1):e000045. DOI:10.1136/bmjresp-2014-000045
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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.
    Innovations Technology and Techniques in Cardiothoracic and Vascular Surgery 04/2014; 9(2). DOI:10.1097/IMI.0000000000000061
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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.
    Journal of Inflammation 03/2014; 11(1):9. DOI:10.1186/1476-9255-11-9 · 2.02 Impact Factor
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    American Journal of Respiratory and Critical Care Medicine 02/2014; 189(4):500-1. DOI:10.1164/rccm.201309-1725LE · 13.00 Impact Factor
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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.
    AJP Lung Cellular and Molecular Physiology 10/2013; 305(12). DOI:10.1152/ajplung.00183.2013 · 4.08 Impact Factor
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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.
    Journal of leukocyte biology 08/2013; 94(6). DOI:10.1189/jlb.0912462 · 4.29 Impact Factor
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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.
    BJA British Journal of Anaesthesia 06/2013; 111(5). DOI:10.1093/bja/aet205 · 4.85 Impact Factor

  • Heart (British Cardiac Society) 05/2013; 99(Suppl 2):A108-A108. DOI:10.1136/heartjnl-2013-304019.193 · 5.60 Impact Factor
  • S. Gallogly · M. Brittan · O. Tura · E. Skinner · N. L. Mills ·

    Heart (British Cardiac Society) 05/2013; 99(Suppl 2):A128-A128. DOI:10.1136/heartjnl-2013-304019.240 · 5.60 Impact Factor
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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.
    American Journal of Respiratory and Critical Care Medicine 04/2013; 188(4). DOI:10.1164/rccm.201212-2334OC · 13.00 Impact Factor
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    ABSTRACT: A decade of research has sought to identify circulating endothelial progenitor cells (EPC) in order to harness their potential for cardiovascular regeneration. Endothelial outgrowth cells (EOC) most closely fulfil the criteria for an EPC, but their origin remains obscure. Our aim was to identify the source and precursor of EOC and to assess their regenerative potential compared to mature endothelial cells. EOC are readily isolated from umbilical cord blood (6/6 donors) and peripheral blood mononuclear cells (4/6 donors), but not from bone marrow (0/6) nor peripheral blood following mobilisation with granulocyte-colony stimulating factor (G-CSF) (0/6 donors). Enrichment and depletion of blood mononuclear cells demonstrated that EOC are confined to the CD34(+) CD133(-) CD146(+) cell fraction. EOC derived from blood mononuclear cells are indistinguishable from mature human umbilical vein endothelial cells (HUVEC) by morphology, surface antigen expression, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), proliferation and functional assessments. In a subcutaneous sponge model of angiogenesis, both EOC and HUVEC contribute to de novo blood vessel formation giving rise to a similar number of vessels (7.0±2.7 versus 6.6±3.7 vessels respectively, n=9. Bone marrow-derived outgrowth cells isolated under the same conditions expressed mesenchymal markers rather than endothelial cell markers and did not contribute to blood vessels in vivo. In this paper, we confirm that EOC arise from CD34(+) CD133(-) CD146(+) mononuclear cells and are similar, if not identical, to mature endothelial cells. Our findings suggest that EOC do not arise from bone marrow and challenge the concept of a bone marrow-derived circulating precursor for endothelial cells.
    Stem Cells 02/2013; 31(2). DOI:10.1002/stem.1280 · 6.52 Impact Factor

  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: Background and Objectives There is increasing evidence that monocytes play a key role in the pathogenesis of acute lung inflammation. Mononuclear cell (MNC) leukapheresis can be used to remove large numbers of monocytes from circulating blood; however, the detailed characteristics of monocyte subpopulations removed by MNC leukapheresis, and the biological effects on the lung, remain incompletely defined. Material and Methods Six healthy male volunteers underwent MNC leukapheresis of four total blood volumes. Blood was collected at 0, 2, 4, 6, 8 and 24 h; bronchoscopy with bronchoalveolar lavage (BAL) was performed at 8–9 h. Multiparameter flow cytometry was used to identify subpopulations of monocytes in blood and monocyte-like cells in BAL fluid. Results A median of 5·57 × 109 monocytes were retrieved. Blood monocyte counts indicated that the circulating blood monocyte pool was actively replenished during leukapheresis and subsequently contained a greater proportion of classical (CD14++ CD16−) monocytes. A particular subpopulation of monocyte-like cells, reminiscent of classical monocytes, was also prominent in BAL fluid after leukapheresis. Conclusion Mononuclear cell leukapheresis was safe. The greater proportion of classical monocytes present in blood after MNC leukapheresis may be clinically significant. MNC leukapheresis also appears to affect the proportion of monocyte-like cells in the lung; however, we found no evidence that leukapheresis has a clinically important pro-inflammatory effect in the human lung.
    Vox Sanguinis 04/2012; 103(4):275-83. DOI:10.1111/j.1423-0410.2012.01611.x · 2.80 Impact Factor

Publication Stats

2k Citations
358.82 Total Impact Points


  • 2010-2014
    • 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