Malcolm Shepherd

University of Glasgow, Glasgow, Scotland, United Kingdom

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Publications (4)23.3 Total impact

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    ABSTRACT: Published information on the effectiveness of bronchial thermoplasty (BT) for severe asthma in 'real life' patients is limited. We compared safety and efficacy outcomes 12 months post procedure in 10 clinic patients and 15 patients recruited to clinical trials of BT at the same centre. Baseline asthma severity was greater in the clinic group. Adverse events were similar. Clinical improvements occurred in 50% of the clinic patients compared with 73% of the research patients. © The Author(s), 2015.
    Therapeutic Advances in Respiratory Disease 08/2015; DOI:10.1177/1753465815601332 · 1.95 Impact Factor
  • Thorax 11/2012; 67(Suppl 2):A65-A66. DOI:10.1136/thoraxjnl-2012-202678.146 · 8.29 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are crucial for the processing of antigens, T lymphocyte priming and the development of asthma and allergy. Smokers with asthma display altered therapeutic behaviour and a reduction in endobronchial DC CD83 expression compared with non-smokers with asthma. No information is available on the impact of smoking on peripheral blood DC profiles. Determine peripheral blood DC profiles in subjects with and without asthma with differing smoking histories. Forty-three asthmatics (17 smokers, nine ex-smokers and 17 never-smokers) and 16 healthy volunteers (nine smokers and seven never-smokers) were recruited. Spirometry, exhaled nitric oxide and venesection was performed. DC elution was by flow cytometry via the expression of DC surface markers [plasmacytoid (pDC) (BDCA-2, CD303), type 1 conventional (cDC) (BDCA-1, CD1c), and type 2 cDC (BDCA-3, CD141)]. Subjects with asthma displayed increases in all DC subtypes compared with normal never-smokers: [type 1 cDCs - asthma [median% (IQR)]: 0.59% (0.41, 0.74), normal never-smokers: 0.35% (0.26, 0.43), P=0.013]; type 2 cDCs - asthma: 0.04% (0.02, 0.06), normal never-smokers: 0.02% (0.01, 0.03), P=0.008 and pDCs - asthma: 0.32% (0.27, 0.46), normal never-smokers: 0.22% (0.17, 0.31), P=0.043, and increased pDC and type 1 cDCs compared with normal smokers. Smoking did not affect DC proportions in asthma. Cigarette smoking reduced pDC proportions in normal subjects [normal never-smokers: 0.22% (0.17, 0.31); normal smokers: 0.09% (0.08, 0.15), P=0.003]. This study shows for the first time that subjects with asthma display a large increase in peripheral blood DC proportions. Cigarette smoking in asthma did not affect the peripheral blood DC profile but did suppress pDC proportions in non-asthmatic subjects. Asthma is associated with a significant increase in circulating DCs, reflecting increased endobronchial levels and the importance of DCs to the development and maintenance of asthma. (Clinical identifier: NCT00411320)
    Clinical & Experimental Allergy 02/2011; 41(5):665-72. DOI:10.1111/j.1365-2222.2010.03692.x · 4.77 Impact Factor
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    M. C. Shepherd · S. R. Sabir · C. McSharry · H. Wulff · P. Bradding
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    ABSTRACT: Introduction and objectives Idiopathic pulmonary fibrosis (IPF) is common, largely unresponsive to treatment with a median survival of 3 years. New therapies are urgently required. IPF is characterised by proliferation of pulmonary mesenchymal cells through epithelial mesenchymal transition, resident fibroblast proliferation and circulating fibrocyte recruitment. We have previously demonstrated that the potassium channel KCa3.1 regulates lung mesenchymal cell proliferation, is up-regulated by TGFβ, an important driver of IPF, and is present in fibrocytes in peripheral blood. We tested the hypotheses that KCa3.1 is up-regulated in IPF using the bleomycin-induced pulmonary fibrosis murine model and that KCa3.1 inhibition reduces pulmonary fibrosis. Methods Prophylactic (Day -3) and daily thereafter, sub-cutaneous TRAM-34, a specific KCa3.1 inhibitor, was administered to C57BL/6 mice later exposed to nasal bleomycin (Day 0) and culled on day +21. Mice exposed to PBS or bleomycin acted as negative and positive controls. The primary endpoint was histological fibrosis score. Inflammation was assessed by bronchoalveolar lavage. Collagen deposition and KCa3.1 expression were assessed by Masson's trichrome staining and qPCR. Results Bleomycin-induced pulmonary fibrosis characterised by thickened alveolar septae, architectural destruction and collagen deposition. Co-administration of TRAM-34 significantly reduced pulmonary fibrosis (Modified Ashcroft's score +/− SEM: 4.8+/−0.8 bleomycin group vs 2.6+/−0.6 TRAM-34 group: p=0.02). Bleomycin increased lung KCa3.1 (55-fold versus PBS control) and collagen Iα mRNA (fourfold) expression (n=3 in each case). Mice receiving bleomycin lost more weight (2.39 vs 0 g) and had greater mortality than those co-administered TRAM-34. BAL cellularity did not differ between the groups. Collagen staining was reduced in the TRAM-34 group. Conclusions KCa3.1 expression is increased in a model of pulmonary fibrosis and inhibition with TRAM-34 significantly improves pathological outcome. The mechanism is likely to involve the modulation of cells involved in the fibrotic process. Previous clinical studies have shown KCa3.1 inhibition to be safe in humans and our study provides a rationale for a clinical trial of KCa3.1 inhibitors in human IPF.
    Thorax 11/2010; 65(Suppl 4):A63-A63. DOI:10.1136/thx.2010.150946.40 · 8.29 Impact Factor