Dr Christopher Scotton

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Name: Christopher Scotton Email: c.scotton@ucl.ac.uk
Title: Dr Tel: 020 7679 6276
Department: Div of Medicine Fax: 020 7679 6973
Position: Honorary Senior Research Associate Address: Centre for Inflammation and Tissue Repair, UCL Respiratory, 5 University Street, London, WC1E 6JF
Research Domain: Basic Life Sciences, Cancer, Experimental Medicine, Infection, Immunology & Inflammation, Personalised Medicine Web Page: Personal Web Page

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Research Description

Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several respiratory conditions, including pulmonary fibrosis. Current dogma assumes that coagulation zymogens are derived from the circulation and locally-activated in response to tissue injury. However, my recent data show for the first time that coagulation factor X (FX) gene expression is significantly upregulated in pulmonary fibrosis and that the bronchial/alveolar epithelium represents a prominent cellular source of FX - the activated form of which (FXa) exerts potent pro-inflammatory/pro-fibrotic effects. These findings herald a paradigm shift in our understanding of the tissue origin of excessive procoagulant signaling in lung disease, and are consistent with the existence of an inducible extravascular lung coagulation system. Our work has also highlighted the involvement of proteinase-activated receptor 1 (PAR1) as the major signaling receptor for coagulation proteinases in the injured lung.

My current research addresses the hypothesis that extravascular pro-coagulant activity, signaling via PAR1, influences innate immune mechanisms and chemokine production to drive the development of lung inflammation and fibrosis. As such, my aims are to determine what regulates the production of extravascular coagulation factors, and how these factors contribute to the establishment of the chemokine networks involved in recruitment of leukocytes and circulating mesenchymal progenitor cells to the injured lung. In addition, I am investigating the significance of pro-coagulant signalling on monocyte/macrophage activation and formation of secondary lymphoid tissue.

This research is being performed using a combination of in vitro and in vivo studies (using both pharmacological and genetic approaches), as well as human biopsy material. The work is being carried out by an active and dynamic group of scientists and clinician scientists at various stages of their academic careers, ranging from PhD student to advanced clinician scientist and is supported by grants obtained from The Medical Research Council, The Wellcome Trust, The British Lung Foundation and The Rosetrees Trust.

Besides expanding our knowledge of the fundamental crosstalk between the coagulation cascade, inflammation and immunity, this work will provide novel insights into the pathophysiological mechanisms underlying lung inflammation and fibrosis. Interfering with FX production or signaling may represent an extremely attractive target for therapeutic intervention in lung injury and fibrosis, and potentially other lung diseases associated with excessive pro-coagulant activity.


Research Activities

Crosstalk between coagulation and immunity

Procoagulant signalling in response to lung injury

Education Description

UCL Collaborators

Prof Rachel Chambers

External Collaborators

Publications

    2014

    • Kallis YN, Scotton CJ, Mackinnon AC, Goldin RD, Wright NA, Iredale JP, Chambers RC, Forbes SJ (2014). Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.. PLoS One, 9(1), e86241 - . doi:10.1371/journal.pone.0086241
    • Baliga RS, Scotton CJ, Trinder SL, Chambers RC, Macallister RJ, Hobbs AJ (2014). Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis.. Br J Pharmacol, , - . doi:10.1111/bph.12694

    2013

    • Scotton CJ, Hayes B, Alexander R, Datta A, Forty EJ, Mercer PF, Blanchard A, Chambers RC (2013). Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation.. Eur Respir J, 42(6), 1633 - 1645. doi:10.1183/09031936.00182412
    • Mercer PF, Williams AE, Scotton CJ, José RJ, Sulikowski M, Moffatt JD, Murray LA, Chambers RC (2013). Proteinase-Activated Receptor-1, CCL2 and CCL7 Regulate Acute Neutrophilic Lung Inflammation.. Am J Respir Cell Mol Biol, , - . doi:10.1165/rcmb.2013-0142OC
    • Garner IM, Evans IC, Barnes JL, Maher TM, Renzoni EA, Denton CP, Scotton CJ, Abraham DJ, McAnulty RJ (2013). Hypomethylation of the TNXB gene contributes to increased expression and deposition of tenascin X in idiopathic pulmonary fibrosis.
    • Garner IM, Evans IC, Maher TM, Renzoni EA, Denton CP, Scotton CJ, Abraham DJ, McAnulty RJ (2013). Genome-wide analysis identifies multiple genes with altered methylation and expression in IPF and SSc lung fibroblasts.
    • Datta A, Alexander R, Sulikowski MG, Nicholson AG, Maher TM, Scotton CJ, Chambers RC (2013). Evidence for a Functional Thymic Stromal Lymphopoietin Signaling Axis in Fibrotic Lung Disease.. J Immunol, , - . doi:10.4049/jimmunol.1300588

    2012

    • Scotton CJ, Chambers RC (2012). Innate immunity in lung fibrosis: a therapeutic role for surfactant protein D?. Am J Respir Crit Care Med, 185(5), 471 - 473. doi:10.1164/rccm.201112-2193ED
    • Jenkins G, Blanchard A, Borok Z, Bradding P, Ehrhardt C, Fisher A, Hirani N, Johnson S, Königshoff M, Maher TM, Millar A, Parfrey H, Scotton C, Tetley T, Thickett D, Wolters P, ECIPF workshop (2012). In search of the fibrotic epithelial cell: opportunities for a collaborative network.. Thorax, 67(2), 179 - 182. doi:10.1136/thoraxjnl-2011-200195
    • McNulty K, Sage EK, Alexander R, Scotton CJ, Janes SM (2012). EXOGENOUS MACROPHAGES ARE RETAINED IN MOUSE LUNGS AFTER INJURY AND TARGET THERAPEUTIC TRANSGENES TO THE INJURED LUNG PARENCHYMA. doi:10.1136/thoraxjnl-2012-202678.135
    • Chambers RC, Scotton CJ (2012). Coagulation cascade proteinases in lung injury and fibrosis.. Proc Am Thorac Soc, 9(3), 96 - 101. doi:10.1513/pats.201201-006AW
    • Smoktunowicz N, Alexander R, Franklin L, Williams AE, Jarai G, Scotton CJ, Mercer PF, Chambers RC (2012). THE EXTRINSIC COAGULATION PATHWAY IS LOCALLY UPREGULATED IN AN EXPERIMENTAL MODEL OF VIRAL EXACERBATION OF PULMONARY FIBROSIS. doi:10.1136/thoraxjnl-2012-202678.133

    2011

    • McNulty K, Scotton CJ, Sage EK, Chambers RC, Janes SM (2011). MACROPHAGES AS VEHICLES FOR DELIVERING CELL THERAPY TO INJURED LUNG. doi:10.1136/thoraxjnl-2011-201054b.73
    • Scotton CJ (2011). A breath of fresh air for tissue engineering?. MATER TODAY, 14(5), 212 - 216.
    • Datta A, Scotton CJ, Chambers RC (2011). Novel therapeutic approaches for pulmonary fibrosis.. Br J Pharmacol, 163(1), 141 - 172. doi:10.1111/j.1476-5381.2011.01247.x
    • Jayasinghe SN, Warnes G, Scotton CJ (2011). Bio-electrosprayed living composite matrix implanted into mouse models.. Macromol Biosci, 11(10), 1364 - 1369. doi:10.1002/mabi.201100131
    • Cho WS, Duffin R, Howie SE, Scotton CJ, Wallace WA, Macnee W, Bradley M, Megson IL, Donaldson K (2011). Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes.. Part Fibre Toxicol, 8, 27 - . doi:10.1186/1743-8977-8-27

    2010

    • Scotton CJ, Chambers RC (2010). Bleomycin revisited: towards a more representative model of IPF?. Am J Physiol Lung Cell Mol Physiol, 299(4), L439 - L441. doi:10.1152/ajplung.00258.2010
    • Alexander RE, Krupiczojc MA, Whitburn J, Alexander S, Chambers RC, Scotton CJ (2010). Production Of Functional Coagulation Factor X (FX) By Human Lung Epithelium Is Upregulated By Oxidative Stress.

    2009

    • Scotton CJ, Krupiczojc MA, Koenigshoff M, Mercer PF, Lee YCG, Kaminski N, Morser J, Post JM, Maher TM, Nicholson AG, Moffatt JD, Laurent GJ, Derian CK, Eickelberg O, Chambers RC (2009). Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. Journal of Clinical Investigation, 119(9), 2550 - 2563.
    • McNulty K, Aguilar S, Scotton CJ, Bonnet D, Janes SM (2009). MURINE HAEMATOPOEITIC STEM CELLS BUT NOT MURINE MESENCHYMAL STEM CELLS AMELIORATE LUNG FIBROSIS USING GENE DELIVERY OF KERATINOCYTE GROWTH FACTOR. doi:10.1136/thx.2009.127076p
    • Aguilar S, Scotton C, Nye E, Stamp G, Laurent G, Bonnet D, Janes S (2009). Bone Marrow Stem Cells Expressing Keratinocyte Growth Factor via an Inducible Lentivirus Protects against Bleomycin-induced Pulmonary Fibrosis. PLoS One, 4(11), e8013 - .
    • Atzori L, Lucatelli M, Scotton CJ, Laurent GJ, Bartalesi B, De Cunto G, Lunghi B, Chambers RC, Lungarella G (2009). Absence of Proteinase Activated Receptor-1 Signaling in Mice Confers Protection from fMLP-induced Goblet Cell Metaplasia.. American Journal of Respiratory Cell and Molecular Biology, , - .
    • Mercer PF, Johns RJ, Scotton CJ, Krupiczojc MA, Howell DCJ, Koenigshoff M, McAnulty RJ, Das A, Thorley AJ, Tetley TD, Eickelberg O, Chambers RC (2009). Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 179(5), 414 - 425.

    2008

    • Deng X, Mercer PF, Scotton CJ, Gilchrist A, Chambers RC (2008). Thrombin induces fibroblast CCL2/JE production and release via coupling of PAR1 to Gαq and cooperation between ERK1/2 and Rho kinase signaling pathways.. Molecular Biology of the Cell, 19(6), 2520 - 2533.
    • Krupiczojc MA, Scotton CJ, Chambers RC (2008). Coagulation signalling following tissue injury: Focus on the role of factor Xa. Int J Biochem Cell Biol., 40(6-7), 1228 - 1237. doi:10.1016/j.biocel.2008.02.026

    2007

    • Scotton CJ, Chambers RC (2007). Molecular targets in pulmonary fibrosis: the myofibroblast in focus.. Chest, 132, 1311 - 1321. doi:10.1378/chest.06-2568
    • Maher TM, Bottoms SE, Mercer PF, Scotton CJ, Thorley A, Wells AU, Nicholson AG, Laurent GJ, Tetley TD, Chambers RC, Mcanulty RJ (2007). Differential modulation of lung fibroblast and alveolar epithelial cell apoptosis by cyclo-oxygenase (COX)-2 and prostaglandin E-2 is an important mechanism in the pathogenesis of idiopathic pulmonary fibrosis.
    • Kallis YN, Scotton CJ, Goldin RD, Russo FP, Chambers RC, Thomas HC, Forbes SJ (2007). PAR-1 knockout bone marrow stem cells can confer an anti-fibrotic phenotype to the injured liver. Journal of Hepatology, 46, 328 - .
    • Kallis YN, Scotton CJ, Goldin RD, Russo FP, Chambers RC, Thomas HC, Forbes SJ (2007). PAR-1 knockout bone marrow stem cells can confer an anti-fibrotic phenotype to the injured liver.
    • Mercer PF, Moffatt JD, Scotton CJ, Derian CK, Chambers RC (2007). Par1 signalling in lipopolysaccharide-induced acute lung injury.

    2006

    • Scotton CJ, Krupiczojc M, Johns RH, Lee YCG, Koenigshoff M, Eickelberg O, Kaminski N, Laurent GJ, Chambers RC (2006). The coagulation cascade in fibrotic lung disease progression: local expression of factor X is increased in the injured and fibrotic lung.
    • Jenkins RG, Su X, Su G, Scotton CJ, Camerer E, Laurent GJ, Davis GE, Chambers RC, Matthay MA, Sheppard D (2006). Ligation of protease-activated receptor 1 enhances alpha(v)beta(6) integrin-dependent TGF-beta activation and promotes acute lung injury. Journal of Clinical Investigation, 116(6), 1606 - 1614.

    2005

    • Krupiczojc MA, Scotton CJ, Laurent GJ, Chambers RC (2005). Activation of PAR1 by FXa induces fibroblast to myofibroblast differentiation.
    • Johns RH, Scotton CJ, Laurent GJ, Chambers RC (2005). PAR1 signaling in lung epithelial cells induces the expression of CCL2/MCP-1 and CTGF.
    • Scotton CJ, Martinez FO, Smelt MJ, Sironi M, Locati M, Mantovani A, Sozzani S (2005). Transcriptional profiling reveals complex regulation of the monocyte IL-1 beta system by IL-13. The Journal of Immunology, 174(2), 834 - 845.
    • Howell DC, Johns RH, Lasky JA, Shan B, Scotton CJ, Laurent GJ, Chambers RC (2005). Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis.. American Journal Of Pathology, 166(5), 1353 - 1365..
    • Scotton C, Locati M, Mantovani A, Sozzani S (2005). Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells - Response. The Journal of Immunology, 174(11), 6561 - 6562.
    • Raes G, Van den BR, De BP, Ghassabeh GH, Scotton C, Locati M, Mantovani A, Sozzani S (2005). Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells. The Journal of Immunology, 174(11), 6561 - 6562.

    2002

    • Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, Bridger G, Balkwill FR (2002). Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Research, 62(20), 5930 - 5938.
    • Milliken D, Scotton C, Raju S, Balkwill F, Wilson J (2002). Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clinical Cancer Research, 8(4), 1108 - 1114.
    • Burke F, Scotton C, Scott KA, Moore R, Arnott C, Balkwill FR (2002). Ovarian cancer. In Jacobs IJ, Shepherd J, Oram D, Hudson C (Ed.), Ovarian cancer (pp. - ). : Oxford University Press, USA.

    2001

    • Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR (2001). Epithelial cancer cell migration: a role for chemokine receptors?. Cancer Research, 61(13), 4961 - 4965.
    • Scotton C, Milliken D, Wilson J, Raju S, Balkwill F (2001). Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours. British Journal of Cancer, 85(6), 891 - 897.

    2000

    • Sica A, Saccani A, Bottazzi B, Bernasconi S, Allavena P, Gaetano B, Fei F, LaRosa G, Scotton C, Balkwill F, Mantovani A (2000). Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. The Journal of Immunology, 164(2), 733 - 738.
    • Scotton C, Burke F (2000). Cytokine Molecular Biology. In Balkwill FR (Ed.), Cytokine Molecular Biology (pp. - ). : Oxford University Press, USA.

    1999

    • Turner L, Scotton C, Negus R, Balkwill F (1999). Hypoxia inhibits macrophage migration. European Journal of Immunology, 29(7), 2280 - 2287.

    • Kallis YN, Scotton CJ, Goldin RD, Thomas HC, Alison MR, Wright NA, Iredale JP, Chambers RC, Forbes SJ (). The bone marrow can modulate liver fibrosis via proteinase-activated receptor-1 signalling on macrophages.. Gut, , - .