Imperial College London

ProfessorPaulElkington

Faculty of MedicineDepartment of Infectious Disease

Honorary Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 2733p.elkington Website

 
 
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Location

 

8N23Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

86 results found

Elkington P, Lerm M, Kapoor N, Mahon R, Pienaar E, Huh D, Kaushal D, Schlesinger LSet al., 2019, In Vitro Granuloma Models of Tuberculosis: Potential and Challenges, JOURNAL OF INFECTIOUS DISEASES, Vol: 219, Pages: 1858-1866, ISSN: 0022-1899

Journal article

Barton E, Gao Y, Ball D, Fidler K, Klein N, Curtis N, Clifford V, Marshall BG, Chancellor A, Mansour S, Elkington P, Tebruegge Met al., 2019, Calcineurin Inhibitors and Variation in the Performance of Interferon-gamma Release Assays Used to Detect Tuberculosis Infection, ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 16, Pages: 771-775, ISSN: 1546-3222

Journal article

Rohlwink UK, Walker NF, Ordonez AA, Li YJ, Tucker EW, Elkington PT, Wilkinson RJ, Wilkinson KAet al., 2019, Matrix metalloproteinases in pulmonary and central nervous system tuberculosis-a review, International Journal of Molecular Sciences, Vol: 20, ISSN: 1422-0067

Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of Mycobacterium tuberculosis bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.

Journal article

Ordonez AA, Pokkali S, Sanchez-Bautista J, Klunk MH, Urbanowski ME, Kubler A, Bishai WR, Elkington PT, Jain SKet al., 2019, Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology, JOURNAL OF INFECTIOUS DISEASES, Vol: 219, Pages: 633-636, ISSN: 0022-1899

Journal article

Elkington PT, Bateman AC, Thomas GJ, Ottensmeier CHet al., 2018, Implications of Tuberculosis Reactivation after Immune Checkpoint Inhibition, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 198, Pages: 1451-1453, ISSN: 1073-449X

Journal article

Bielecka MK, Elkington P, 2018, Advanced cellular systems to study tuberculosis treatment, CURRENT OPINION IN PHARMACOLOGY, Vol: 42, Pages: 16-21, ISSN: 1471-4892

Journal article

Ong C, Fox K, Ettorre A, Elkington P, Friedland JSet al., 2018, Hypoxia increases neutrophil-driven matrix destruction after exposure to mycobacterium tuberculosis, Scientific Reports, Vol: 8, ISSN: 2045-2322

The importance of neutrophils in the pathology of tuberculosis (TB) has been recently established. We demonstrated that TB lesions in man are hypoxic, but how neutrophils in hypoxia influence lung tissue damage is unknown. We investigated the effect of hypoxia on neutrophil-derived enzymes and tissue destruction in TB. Human neutrophils were stimulated with M. tuberculosis (M.tb) or conditioned media from M.tb-infected monocytes (CoMTB). Neutrophil matrix metalloproteinase-8/-9 and elastase secretion were analysed by luminex array and gelatin zymography, gene expression by qPCR and cell viability by flow cytometry. Matrix destruction was investigated by confocal microscopy and functional assays and neutrophil extracellular traps (NETs) by fluorescence assay. In hypoxia, neutrophil MMP-8 secretion and gene expression were up-regulated by CoMTB. MMP-9 activity and neutrophil elastase (NE) secretion were also increased in hypoxia. Hypoxia inhibited NET formation and both neutrophil apoptosis and necrosis after direct stimulation by M.tb. Hypoxia increased TB-dependent neutrophil-mediated matrix destruction of Type I collagen, gelatin and elastin, the main structural proteins of the human lung. Dimethyloxalylglycin (DMOG), which stabilizes hypoxia-inducible factor-1α, increased neutrophil MMP-8 and -9 secretion. Hypoxia in our cellular model of TB up-regulated pathways that increase neutrophil secretion of MMPs that are implicated in matrix destruction.

Journal article

Urbanowski ME, Ihms EA, Bigelow K, Kubler A, Elkington PT, Bishai WRet al., 2018, Repetitive Aerosol Exposure Promotes Cavitary Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction, JOURNAL OF INFECTIOUS DISEASES, Vol: 218, Pages: 53-63, ISSN: 0022-1899

Journal article

Tebruegge M, Curtis N, Clifford V, Fernandez-Turienzo C, Klein N, Fidler K, Mansour S, Elkington P, Morris-Jones Set al., 2018, Seasonal variation in the performance of QuantiFERON-TB Gold In-Tube assays used for the diagnosis of tuberculosis infection, TUBERCULOSIS, Vol: 110, Pages: 26-29, ISSN: 1472-9792

Journal article

Tebruegge M, Elkington PT, 2018, Cytokine diagnosis of pleural TB: will it stand the test of time?, THORAX, Vol: 73, Pages: 206-207, ISSN: 0040-6376

Journal article

Singh S, Maniakis-Grivas G, Singh U, Asher R, Mauri F, Elkington P, Friedland JSet al., 2018, Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis, Journal of Pathology, Vol: 244, Pages: 311-322, ISSN: 0022-3417

Tuberculosis (TB) is characterised by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T helper-17 (TH-17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC) and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and TH-17 cytokines. MMP secretion, activity and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p<0.001) over 72 h whilst decreasing that of MMP-9 (p<0.0001); mRNA levels were similarly affected. Both IL-17 and Interleukin-22 (IL-22) increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not Interleukin-23 (IL-23), were significantly upregulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI 3-K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3-K pathways.

Journal article

Bishai WR, Urbanowski M, Ihms E, Bigelow K, Kubler A, Elkington PTet al., 2018, Repetitive Aerosol Exposure Promotes Lung Pathology and Cavitation in Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Chancellor A, Tocheva AS, Cave-Ayland C, Tezera L, White A, Al Dulayymi JR, Bridgeman JS, Tews I, Wilson S, Lissin NM, Tebruegge M, Marshall B, Sharpe S, Elliott T, Skylaris C-K, Essex JW, Baird MS, Gadola S, Elkington P, Mansour Set al., 2017, CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 114, Pages: E10956-E10964, ISSN: 0027-8424

Journal article

Edwards A, Gao Y, Allan RN, Ball D, de Graaf H, Coelho T, Clifford V, Curtis N, Williams A, Faust SN, Mansour S, Marshall B, Elkington P, Tebruegge Met al., 2017, Corticosteroids and infliximab impair the performance of interferon-gamma release assays used for diagnosis of latent tuberculosis, THORAX, Vol: 72, Pages: 946-949, ISSN: 0040-6376

Journal article

Clayton K, Polak ME, Woelk CH, Elkington Pet al., 2017, Gene Expression Signatures in Tuberculosis Have Greater Overlap with Autoimmune Diseases Than with Infectious Diseases, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 196, Pages: 655-656, ISSN: 1073-449X

Journal article

Tezera LB, Bielecka MK, Elkington PT, 2017, Bioelectrospray Methodology for Dissection of the Host-pathogen Interaction in Human Tuberculosis, BIO-PROTOCOL, Vol: 7

Journal article

Chancellor A, White A, Tocheva AS, Fenn JR, Dennis M, Tezera L, Singhania A, Elliott T, Tebruegge M, Elkington P, Gadola S, Sharpe S, Mansour Set al., 2017, Quantitative and qualitative iNKT repertoire associations with disease susceptibility and outcome in macaque tuberculosis infection, TUBERCULOSIS, Vol: 105, Pages: 86-95, ISSN: 1472-9792

Journal article

Brace P, Tezera L, Bielecka M, Mellows T, Garay D, Tian S, Rand L, Green J, Jogai S, Steele A, Millar T, Sanchez-Elsner T, Friedland J, Proud C, Elkington Pet al., 2017, Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology, PLOS Pathogens, Vol: 13, ISSN: 1553-7366

Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.

Journal article

Moores R, Dos Santos Brilha S, Schutgens F, Elkington P, Friedland JSet al., 2017, Epigenetic regulation of Matrix metalloproteinase-1 and -3 expression in mycobacterium tuberculosis infection, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224

In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between −2,001 and −2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance.

Journal article

Walker NF, Wilkinson KA, Meintjes G, Tezera LB, Goliath R, Peyper JM, Tadokera R, Opondo C, Coussens AK, Wilkinson RJ, Friedland JS, Elkington PTet al., 2017, Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study, Clinical Infectious Diseases, Vol: 65, Pages: 121-132, ISSN: 1058-4838

Background. Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, butthe underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a keyprocess but has not been systematically studied in HIV-associated TB.Methods. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)–infected and –uninfected TB patientsand controls, and a prospective cohort study of HIV-1–infected TB patients at risk of TB immune reconstitution inflammatorysyndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasmaprocollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM)by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacteriumtuberculosis and extracellular matrix in a 3D model of TB granuloma formation.Results. MMP activity differed between HIV-1–infected and –uninfected TB patients and corresponded with specific TB clinicalphenotypes. HIV-1–infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation,but increased plasma PIIINP, compared to HIV-1–uninfected TB patients. Elevated extrapulmonary extracellular matrix turnoverwas associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likelyneutrophil derived and M. tuberculosis–antigen driven. Mycobacterium tuberculosis–induced matrix degradation was suppressed bythe MMP inhibitor doxycycline in vitro.Conclusions. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrixturnover in HIV-1–infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibitionis a potential host-directed therapy

Journal article

Bielecka MK, Tezera LB, Zmijan R, Drobniewski F, Zhang X, Jayasinghe S, Elkington Pet al., 2017, A bioengineered three-dimensional cell culture platform integrated with microfluidics to address antimicrobial resistance in tuberculosis, MBIO, Vol: 8, ISSN: 2150-7511

Antimicrobial resistance presents one of the most significant threats to human health, with the emergence of totally drug-resistant organisms. We have combined bioengineering, genetically modified bacteria, longitudinal readouts, and fluidics to develop a transformative platform to address the drug development bottleneck, utilizing Mycobacterium tuberculosis as the model organism. We generated microspheres incorporating virulent reporter bacilli, primary human cells, and an extracellular matrix by using bioelectrospray methodology. Granulomas form within the three-dimensional matrix, and mycobacterial stress genes are upregulated. Pyrazinamide, a vital first-line antibiotic for treating human tuberculosis, kills M. tuberculosis in a three-dimensional culture but not in a standard two-dimensional culture or Middlebrook 7H9 broth, demonstrating that antibiotic sensitivity within microspheres reflects conditions in patients. We then performed pharmacokinetic modeling by combining the microsphere system with a microfluidic plate and demonstrated that we can model the effect of dynamic antibiotic concentrations on mycobacterial killing. The microsphere system is highly tractable, permitting variation of cell content, the extracellular matrix, sphere size, the infectious dose, and the surrounding medium with the potential to address a wide array of human infections and the threat of antimicrobial resistance.

Journal article

Ong C, Pabisiak P, Dos Santos Brilha S, Singh P, Roncaroli F, Elkington P, Friedland Jet al., 2017, Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis, Journal of Neuroinflammation, Vol: 14, ISSN: 1742-2094

BackgroundCentral nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined.MethodsHuman brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors.ResultsMMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not.ConclusionsMultiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB.

Journal article

Tezera LB, Bielecka MK, Chancellor A, Reichmann MT, Al Shammari B, Brace P, Batty A, Tocheva A, Jogai S, Marshall BG, Tebruegge M, Jayasinghe SN, Mansour S, Elkington PTet al., 2017, Dissection of the host-pathogen interaction in human tuberculosis using a bioengineered 3-dimensional model, ELIFE, Vol: 6, ISSN: 2050-084X

Journal article

Goldklang M, Reed RM, Xiao R, Stearns K, Cvetkovski F, Turne D, Zelonina T, Trischler J, Elkington P, Farber DL, D'Armiento JMet al., 2017, Essential Role For Mmp-13 In Lung Destruction Of COPD Exacerbations, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Elkington P, Tebruegge M, Mansour S, 2016, Tuberculosis: An Infection-Initiated Autoimmune Disease?, TRENDS IN IMMUNOLOGY, Vol: 37, Pages: 815-818, ISSN: 1471-4906

Journal article

Brilha S, Sathyamoorthy T, Stuttaford LH, Walker NF, Wilkinson RJ, Singh S, Moores RC, Elkington PT, Friedland JSet al., 2016, ESAT-6 Drives MMP-10 Gene Expression and Secretion in Tuberculosis., American Journal of Respiratory Cell and Molecular Biology, Vol: 56, Pages: 223-232, ISSN: 1535-4989

Tuberculosis (TB) causes disease worldwide and multi-drug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb) infected macrophages and in conditioned medium from Mtb infected monocytes (CoMtb)-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, while CoMtb increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of TB patients from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared to controls and patients with other respiratory diseases (both p<0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain BCG (p<0.001), whereas both mycobacteria upregulated TNFα secretion equally. Using overlapping short linear peptides covering the sequence of ESAT-6, a virulence factor secreted by Mtb but not BCG, we found that stimulation of human macrophages with a single specific 15 amino acid peptide sequence drove 3-fold greater MMP-10 secretion than any other peptide (p<0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and ERK MAPK blockade (p<0.001 and p<0.01 respectively), but was not affected by inhibition of NF-ĸB. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10 and this is partly driven by the virulence factor ESAT-6, implicating it in TB-associated tissue destruction.

Journal article

Ostridge K, Williams N, Kim V, Harden S, Bourne S, Coombs NA, Elkington PT, Estepar RS, Washko G, Staples KJ, Wilkinson TMet al., 2016, Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases., Respiratory Research, Vol: 17, ISSN: 1465-993X

BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function. METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types. RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs. CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism. TRIAL REGISTRATION: Tri

Journal article

Belton M, dos santos Brilha S, Manavaki R, Mauri F, Nijran K, Hong YT, Patel N, Dembek M, Tezera L, Green J, Moores R, Aigbirhio F, Al-Nahhas A, Fryer T, Elkington P, Friedland JSet al., 2016, Hypoxia and tissue destruction in pulmonary tuberculosis, Thorax, Vol: 71, Pages: 1145-1153, ISSN: 1468-3296

Background: It is unknown whether lesions in human tuberculosis (TB) are hypoxic or whether this influences disease pathology. Human TB is characterized by extensive lung destruction driven by host MMPs, particularly collagenases such as MMP-1. Methods: We investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by siRNA inhibition.Results: [18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine, a small molecule inhibitor which stabilises the transcription factor Hypoxia Inducible Factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multi-nucleate giant cells express HIF-1α. HIF-1α blockade including by targeted siRNA inhibited TB-driven MMP-1 gene expression and secretion. Conclusions: Human TB lesions are severely hypoxic and M.tb drives HIF- 1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation

Journal article

Mansour S, Tocheva AS, Cave-Ayland C, Machelett MM, Sander B, Lissin NM, Molloy PE, Baird MS, Stuebs G, Schroeder NWJ, Schumann RR, Rademann J, Postle AD, Jakobsen BK, Marshall BG, Gosain R, Elkington PT, Elliott T, Skylaris C-K, Essex JW, Tews I, Gadola SDet al., 2016, Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 113, Pages: E1266-E1275, ISSN: 0027-8424

Journal article

Kubler A, Larsson C, Luna B, Andrade BB, Amaral EP, Urbanowski M, Orandle M, Bock K, Ammerman NC, Cheung LS, Winglee K, Halushka M, Park JK, Sher A, Friedland JS, Elkington PT, Bishai WRet al., 2016, Cathepsin K Contributes to Cavitation and Collagen Turnover in Pulmonary Tuberculosis, JOURNAL OF INFECTIOUS DISEASES, Vol: 213, Pages: 618-627, ISSN: 0022-1899

Journal article

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