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1. Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation.

Author

Khedoe, P. P. S. J., van Schadewijk, W. A. A. M., Schwiening, M., Ng-Blichfeldt, J. P., Marciniak, S. J., Stolk, J., Gosens, R., and Hiemstra, P. S.

Subjects
UNFOLDED protein response, CHRONIC obstructive pulmonary disease, CIGARETTE smoke, SMOKING, FIBROBLASTS, WNT genes
Abstract

Adequate lung epithelial repair relies on supportive interactions within the epithelial niche, including interactions with WNT-responsive fibroblasts. In fibroblasts from patients with chronic obstructive pulmonary disease (COPD) or upon in vitro cigarette smoke exposure, Wnt/ß-catenin signalling is distorted, which may affect interactions between epithelial cells and fibroblasts resulting in inadequate lung repair. We hypothesized that cigarette smoke (CS), the main risk factor for COPD, interferes with Wnt/ß-catenin signalling in fibroblasts through induction of cellular stress responses, including oxidative- and endoplasmic reticulum (ER) stress, and thereby alters epithelial repair support potential. Therefore, we assessed the effect of CS-exposure and the ER stress inducer Thapsigargin (Tg) on Wnt/ß-catenin signalling activation in MRC-5 fibroblasts, and on their ability to support lung epithelial organoid formation. Exposure of MRC-5 cells for 15 min with 5 AU/mL CS extract (CSE), and subsequent 6 h incubation induced oxidative stress (HMOX1). Whereas stimulation with 100 nM Tg increased markers of both the integrated stress response (ISR - GADD34/PPP1R15A, CHOP) and the unfolded protein response (UPR - XBP1spl, GADD34/PPP1R15A, CHOP and HSPA5/BIP), CSE only induced GADD34/PPP1R15A expression. Strikingly, although treatment of MRC-5 cells with the Wnt activator CHIR99021 upregulated the Wnt/ß-catenin target gene AXIN2, this response was diminished upon CSE or Tg pre-exposure, which was confirmed using a Wnt-reporter. Furthermore, pre-exposure of MRC-5 cells to CSE or Tg, restricted their ability to support organoid formation upon co-culture with murine pulmonary EpCam+ cells in Matrigel at day 14. This restriction was alleviated by pre-treatment with CHIR99021. We conclude that exposure of MRC-5 cells to CSE increases oxidative stress, GADD34/PPP1R15A expression and impairs their ability to support organoid formation. This inhibitory effect may be restored by activating the Wnt/ß-catenin signalling pathway. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Patterns and characterization of COPD exacerbations using real-time data collection

Author

Ejiofor SI, Stolk J, Fernandez P, and Stockley RA

Subjects
Exacerbations, Alpha-1 antitrypsin deficiency, COPD, Diseases of the respiratory system, RC705-779
Abstract

Stanley I Ejiofor,1,2 Jan Stolk,3 Pablo Fernandez,4 Robert A Stockley1,2 1Centre for Translational Inflammation Research, University of Birmingham, 2ADAPT Project, University Hospital Birmingham, Birmingham, UK; 3Leiden University Medical Centre, Leiden, the Netherlands; 4Independent consultant, Penn, UK Introduction: Patients with chronic obstructive pulmonary disease often experience exacerbations. These events are important as they are a major cause of morbidity and mortality. Recently, it has been increasingly recognized that patients may experience symptoms suggestive of an exacerbation but do not seek treatment, which are referred to as unreported or untreated exacerbations. Symptom diaries used in clinical trials have the benefit of identifying both treated and untreated exacerbation events. Methods: The Kamada study was a multicenter, double-blind randomized controlled trial of inhaled augmentation therapy in alpha-1 antitrypsin deficiency (AATD). A retrospective review of daily electronic symptom diary cards was undertaken from the two leading centers to identify symptomatic episodes consistent with a definition of an exacerbation. The aims were to explore the relationship between exacerbation events and classical “Anthonisen” symptoms and to characterize treated and untreated episodes. Results: Forty-six AATD patients with airflow obstruction and history of exacerbations were included in the analysis. Two hundred thirty-three exacerbation episodes were identified: 103 untreated and 130 treated. Untreated episodes were significantly shorter (median 6 days; interquartile range [IQR] 3–10 days) than the treated episodes (median 10 days; IQR 5–18.25 days: P

Published
2017

6. Abstracts of poster presentations

Author

Agostinho, A. B., Rosi, F., Tabucchi, A., Carlucci, F., Pizzichini, M., Arnér, Elias S. J., Eriksson, Staffan, Barankiewicz, J., Trembacz, H., Zwierzchowski, L., Bergman, A. M., van Haperen, V. W. T. Ruiz, Veerman, G., Vermorken, J. B., Peters, G. J., Bory, C., Chantin, C., Rocca, J. L., Bzowska, A., Ananlev, A. V., Ramzaeva, N., Alksins, E., Maurins, J. A., Kulikowska, E., Shugar, D., Davies, P. M., Fairbanks, L. D., Simmonds, H. A., De Graaf, T. W., Van Dijk, W., de Jong D., Huysmans F., De Abreu R., Monnens L., Dijkman H., van Liebergen F., Assmann K., Duley, J. A., Hanefeld, F., Fabianowska-Majewska, K., Duley, A. J., Greger, J., Wasiak, T., Gathof, B. S., Ried, T., Zwieauer, K., Gresser, U., Griesmacher, A., Weigel, G., Müller, M. M., Gross, M., Empl, W., Guisan, B., Roch-Ramel, F., Harley, E. H., Baumgarten, I., Kaletha K., Nagel-Starczynowska G., Karlsson, Anna, Lambooy, L., Boerbooms, A., De Abreu, R., van de Putte, L., Stolk, J., vd Pulte, L., Komissarov, A. A., Romanova, D. V., Debabov, V. G., Kozlov, A. M., Sokolov, V. B., Aksinenko, A. Y., Fetisov, V. I., Komoriya, Keiji, Osada, Yoshio, Hasegawa, Masaichi, Kondo, Shiro, Couch, Ronald C., Griffin, Travis B., Lakaschus, G., Löffler, H. G., Löffler, M., Jiménez, M. López, Salinero, M. A., Guilarte, J. Sánchez, Matesanz, J. Perianes, Medina, L. Vigil, Galiana, J. Ruiz, Marlewski, M., Smolenski, R. T., Swierczynski, J., Rutkowski, B., Zydowo, M. M., Micheli, V., Pescaglini, M., Sestini, S., Jacomelli, G., Magagnoli, C., Pompucci, G., Hayek, G., Mimouni, M., Boptemps, F., Van den Berghe, G., Miranda, M. E., Mateos, F. A., Herrero, E., González, A., Puig, J. G., Miscetti, P., Minelli, A., Proietti, A., Moroni, M., Mezzasoma, I., Moro, J. F., Noam, I., Cameron, J. S., McBride, M. B., Mathew, C. G. P., Ogg, C. S., Puig, J. G., Miranda, M. E., Mateos, F. A., Luzi, L., Noordhuis, P., Kazemier, K., Kaspers, G. J. L., Overgaard-Hansen, K., Marcussen, M., Klenow, H., Pelatti, A., Quaratino, C. P., D'Amario, C., Tentarelli, R., Giacomello, A., Rocchigiani, M., Iacomelli, G., Pandolfi, M. L., Arezzini, L., Terzuoli, L., Pagani, R., Di Sciascio, N., Colosimo, A., Ranieri-Paggi, M., Ronca, F., Brown, P. E., Moir, A. J. G., Raggi, A., Schwendel A., Grune T., Siems W. G., Holzhuetter H. G., Sebesta, I., Krijt, J., Vondrak, K., Kmoch, S., Hrebicek, M., Senatore, G., Del Lucchese, G., Martini, C., Lucacchini, A., Siems, W. G., Mertsch, K., Blasig, I., Grune, T., Skladanowski, A. C., Hoffmann, C. S., Krass, J. D., Makarewicz, W., Jastorff, B., Slingerland, R. J., Bodlaender, J. M., Van Lenthe, H., Elzinga, L., Van Kuilenburg, A. B. P., Voûte, P. A., Van Gennip, A. H., Smid, K., van der Wilt, C. L., Aherne, G. W., Pinedo, H. M., Sorqi, M. L., Rucci, C., Zoppini, A., Staub M., Sasvári-Székely M., Spasokukockaja T., Hrabák A., Stolk, J. N., De Abreu, R. A., De Koning, D. G. M., Lambooy, L. H. M., Kerstens, P. J. S. M., Boerbooms, A. M. Th., van de Putte, L. B. A., Szüts, P., Szirovicza, éva, åbrahám, C. S., Havass, Z., Jezewska, M. M., Van Acker, K. J., Eyskens, F. J., Verkerk, R. H., Scharpé, S. S., van Kuppevelt, T. H., Veerkamp, J. H., Sabina, R. L., Van Laar J. A. M., Mayhew E., Durrani F. A., Peters G. J., Rustum Y. M., Wang, J. Z., Leoncini, R., Vannoni, D., and Marinello, E.

Published
1993
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24. [alpha]sub-1-Antitrypsin deficiency o 7: Computed tomographic imaging in [alpha]sub-1-antitrypsin deficiency

Author

Shaker, S.B., Stavngaard, T., Stolk, J., Stoel, B., and Dirksen, A.

Subjects
Smoking -- Risk factors, Glycoproteins -- Health aspects, Glycoproteins -- Care and treatment, Glycoproteins -- Research, Emphysema, Pulmonary -- Development and progression, Emphysema, Pulmonary -- Research, Emphysema, Pulmonary -- Causes of, Emphysema, Pulmonary -- Diagnosis, Tomography, Quality of life, Pulmonary function tests, Health
Published
2004

39. Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease

Author

Lapperre, T. S., Snoeck-Stroband, J. B., Gosman, M. M. E., Jansen, D. F., Schadewijk, A., Thiadens, H. A., Vonk, J. M., Boezen, H. M., Ten Hacken, N. H. T., Sont, J. K., Rabe, K. F., Kerstjens, H. A. M., Hiemstra, P. S., Wim Timens, Postma, D. S., Sterk, P. J., Kauffman, H. F., Reus, D., Barentsen, M. D. W., Zeinstra-Smit, M., Luteijn, A. J., Molen, T., Ter Veen, G., Maaren, M. S., Veltman, C. A., Verbokkem, A., Verhage, I., Vink-Klooster, H. K., Gast-Strookman, J., Janssen, K., Schrumpf, J. A., Smit-Bakker, J., Stolk, J., Tiré, A. C. J. A., Veen, H., Wijffels, M. M. E., Willems, L. N. A., Mauad, T., GLUCOLD Study Grp, Internal Medicine, Epidemiology, Surgery, Erasmus MC other, Pharmacy, Department of Strategic Management and Entrepreneurship, AII - Amsterdam institute for Infection and Immunity, and Pulmonology

Subjects
Male, medicine.medical_specialty, medicine.drug_class, Bronchi, Cell Count, Placebo, Gastroenterology, Fluticasone propionate, Drug Administration Schedule, Pulmonary function testing, Pulmonary Disease, Chronic Obstructive, Bronchodilator, Internal medicine, Forced Expiratory Volume, Administration, Inhalation, Internal Medicine, Medicine, Humans, Albuterol, Lung, Salmeterol Xinafoate, Fluticasone, Asthma, Aged, Inflammation, COPD, business.industry, Smoking, Sputum, General Medicine, Middle Aged, medicine.disease, Surgery, Bronchodilator Agents, Androstadienes, Treatment Outcome, Drug Therapy, Combination, Female, Salmeterol, Human medicine, business, medicine.drug
Abstract

Background: Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 μg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 μg twice daily, and salmeterol, 50 μg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (-55% [95% CI, -74% to -22%]; P - 0.004), CD4- cells (-78% [CI, -88% to 60%]; P < 0.001), CD8+ cells (-57% [CI, -77% to -18%]; P = 0.010), and mast cells (-38% [CI, -60% to -2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.

Published
2009

43. Preface

Author

Giacomello, Alessandro, Peters, G. J., Eriksson, Staffan, De Abreu, Ronney, Kristensen, T., Munch-Petersen, B., Vincenzetti, S., Cambi, A., Neuhard, J., Garattini, E., Vita, A., Oka, J., Matsumoto, A., Hosokawa, Y., Inoue, S., Allegrini, S., Johnson, R. B., Fiol, C. J., Eriksson, S., Fabianowska-Majewska, K., Wasiak, T., Duley, J., Simmonds, A., Bretner, M., Felczak, K., Poznański, J., Dzik, J. M., Golos, B., Jarmuła, A., Rode, W., Kulikowski, T., Codacci-Pisanelli, G., Pinedo, H. M., Noordhuis, P., van Groeningen, C. J., van der Wilt, C. L., Franchi, F., Hatse, S., Balzarini, J., De Clercq, E., Marinello, E., Rosi, F., Dispensa, E., Mangiavacchi, P., Riario-Sforza, G., Agostinho, A. B., Smolenski, R. T., Müller, Mathias M., Roch-Ramel, F., Guisan, B., Diezi, J., Tavenier, M., Skladanowski, A. C., de Abreu, R. A., de Jong, J. W., Åmellem, Øystein, Löffler, Monika, Pettersen, Erik O., Boulieu, R., Lenoir, A., Bertocchi, M., Mornex, J. F., Makarewicz, W., Spychala J., Mitchell B. S., Barankiewcz J., Góra-Tybor, Joanna, Robak, Tadeusz, Spasokukotskaja T., Sasvári-Székely M., Piróth Zs., Kazimierczuk Z., Staub M., Keuzenkamp-Jansen, C W, De Abreu, R A, Bökkerink, J P M, Trijbels, J M F, Eriksson S., Warzocha, K., Krykowski, E., Góra-Tybor, J., Fronczak, A., Robak, T., Minelli, A., Moroni, M., Monacelli, N., Mezzasoma, I., Amici, A., Emanuelli, M., Raffaelli, N., Ruggieri, S., Magni, G., Carta, M. C., Mattana, A., Poddie, F., Sgarrella, F., Tozzi, M. G., Veerman, G., Ruiz van Haperen, V. W. T., van Moorsel, C. J. A., Pesi, R., Baiocchi, C., Camici, M., Ipata, P. L., Kozłowska, M., Świerczyński, J., Smoleński, R. T., Jastorff, B., Messina, E., Savini, F., Procopio, A., Giacomello, A., Wielgus-Kutrowska, B., Kulikowska, E., Wierzchowski, J., Bzowska, A., Shugar, D., Fairbanks, Lynette D, Ruckemann, Katarzyna, Simmonds, H Anne, Kaletha, K., Szymańska, G., Thebault, M., Raffin, J. P., Le Gal, Y., Griesmacher, Andrea, De Abreu, Ronney A., Zych, M., Ruckemann, K., Jagodzinski, P., Kochan, Z., Stolk, J., Boerbooms, A., De Abreu, R., de Koning, D., van de Putte, L., Fiorini, M., Bazzichi, L., Bertolini, G., Martini, C., Ciompi, M. L., Lucacchini, A., Pizzichini, M., Terzuoli, L., Arezzini, L., Fe, L., Pagani, R., Miscetti, P., Allegrucci, C., Sebesta, I., Duley, J. A., Simmonds, H. A., Gross, M., Salerno, C., Stone, T. W., Van den Berghe, G., Valik, Dalibor, Jones, James D., Guerranti, R., Fè, L., Sforza, G. Riario, Knecht, Wolfgang, Grein, Klaus, Lodi, R., Iotti, S., Barbiroli, B., Bonin, B., Chantin, C., Bory, C., Micheli, V., Jacomelli, G., Morozzi, G., Fioravanti, A., Marcolongo, R., Pompucci, G., Peters G J, Noordhuis P, Komissarov A, Holwerda U, Kok R M, Van Laar J A M, Van der Wilt C L, Van Groeningen C J, Pinedo H M, Perrett, David, Jacobsson, Bengt, Sisto A., Iezzi A., Di Carlo M., Pizzigallo E., Akhondzadeh, S., MacGregor, D. G., Ogilvy, H. V., Zoref-Shani, E., Brosh, S., Sidi, Y., Bromberg, Y., Sperling, O., van Gennip, A. H., Abeling, N. G. G. M., Stroomer, A. E. M., van Lenthe, H., Bakker, H. D., van Kuilenburg, A. B. P., Connolly, G. P., Abbott, N. J., Lilling, G., Gozes, I., Vreken, P., Meinsma, R., de Ahreu, R. A., Diasio, R. B., Albin, N., Johnson, M. R., Shahinian, H., Wang, K., Gathof, B. S., Rocchigiani, M., Puig, J. G., Mateos, F., Sestini, S., Krijt, J., Shin, Y., Gresser, U., Costa, A., Maximova, N., Andolina, M., Paci, M., Carrozzi, M., Osbich, A., Durighello, M., Cavalli, F., Geatti, O., Zammarchi, E., Morgan, Gareth, Webster, A. D. B., Slavin, S., Naparstek, E., Nagler, A., Acker, M., Cividalli, G., Kapellushnik, Y., Varadi, G., Ben-Yoseph, R., Or, R., Parfenov, V. V., Ignatenko, M. A., Amchenkova, A. M., Narovlyansky, A. N., Spoto, G., Mastropasqua, L., Gizzi, F., Arduini, A., Del Gallo, P., Ciancaglini, M., Gallenga, P. E., Šebesta, I., Zeman, J., Crifò, C., Di Vito, M., Lomonte, A., Gerber, G., Carlucci, F., Tabucchi, A., Vannoni P., Di Pietro M. C., Vincent, M. F., Bontemps, F., Boer, P., Rötzer, E., Ehrmann, D., Empl, W., Bride, M. B. Mc, Ogg, C. S., Cameron, J. S., Moro, F., Rigden, S., Rees, L., Hoff, W. Van't, Raman, V., Palmieri, P., Mastropierro, G., Albertazzi, A., Rucci, C., Darlington, L. G., Cotton, S. R., de Gorter, J. J., Lawrence, E. S., Petrie, A., Sarsam, R. P., Semple, M. J., Warburton, E. A., Quaratino, C. P., Talone, L., Di Sciascio, N., Hrebíček, M. H., Poupětová, H., Ledvinová, J., Elleder, M., Vondrák, K., Rees, P. C., Wonke, B., Thein, S. L., Clegg, J. B., Marlewski, M., Pennelli, A., Di Marzio, M., Angelini, G., Sabatino, G., de Koning, P., Kerstens, P., de Graaf, R., Hayek, G., and Cardona, F.

Published
1995
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45. PS-142 - Liver fibrosis and metabolic alterations in adults with homozygous alpha1-antitrypsin deficiency (PiZZ genotype)

Author

Hamesch, K., Woditsch, V., Mandorfer, M., Moeller, L.S., Pereira, Vítor, Delgado, M.P., Reichert, M.C., Heimes, C.V., Voss, J., Spivak, I., Gueldiken, N., Arslanow, A., Schaefer, B., Zoller, H., Aigner, E., Reiberger, T., Martin, W., Siegmund, B., Eray, Y., Danilo, B., Stolk, J., Gleiber, W., Knipel, V., Windisch, W., Bals, R., Koczulla, A.R., Miravitlles, M., Janciauskiene, S., Genesca, J., Lammert, F., Trauner, M., Krag, A., Trautwein, C., and Strnad, P.

Published
2018
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49. Toll-Like Receptor (TLR2 and TLR4) Polymorphisms and Chronic Obstructive Pulmonary Disease

Author

Budulac, Simona E., Boezen, H. Marike, Hiemstra, Pieter S., Lapperre, Therese S., Vonk, Judith M., Timens, Wim, Postma, Dirkje S., Kauffman, H. F., de Reus, D., Jansen, D. F., Barentsen, M. D.W., Zeinstra-Smit, M., Luteijn, A. J., van der Molen, T., ter Veen, G., Gosman, M. M.E., ten Hacken, N. H.T., Kerstjens, H. A.M., van Maaren, M. S., Veltman, C. A., Verbokkem, A., Verhage, I., Vink-Klooster, H. K., Snoeck-Stroband, J. B., Thiadens, H., Sont, J. K., Bajema, I., Gast-Strookman, J., Janssen, K., Rabe, K. F., van Schadewijk, A., Smit-Bakker, J., Stolk, J., Tire', A. C.J.A., van der Veen, H., Wijffels, M. M.E., Willems, L. N.A., Sterk, P. J., Mauad, T., GLUCOLD Study Grp, Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Erasmus School of Economics, Internal Medicine, Epidemiology, Surgery, Erasmus MC other, Pharmacy, Department of Strategic Management and Entrepreneurship, AII - Amsterdam institute for Infection and Immunity, and Pulmonology

Subjects
Male, Pulmonology, Chronic Obstructive Pulmonary Diseases, Pulmonary function testing, Pulmonary Disease, Chronic Obstructive, Pathology, Longitudinal Studies, TOLL-LIKE-RECEPTOR-2 EXPRESSION, Lung, SNPS, COPD, Multidisciplinary, Middle Aged, medicine.anatomical_structure, Medicine, Female, medicine.symptom, Engineering sciences. Technology, Research Article, Clinical Research Design, Science, Inflammation, Single-nucleotide polymorphism, Models, Biological, Polymorphism, Single Nucleotide, SALMETEROL, Diagnostic Medicine, Genetics, medicine, Humans, Biology, Aged, Polymorphism, Genetic, business.industry, Sputum, Immunity, medicine.disease, GENE, Toll-Like Receptor 2, respiratory tract diseases, Toll-Like Receptor 4, TLR2, Gene Expression Regulation, CIGARETTE-SMOKE, Genetics of Disease, Immunology, CELLS, Genetic Polymorphism, TLR4, Clinical Immunology, business, Population Genetics, Biomarkers, General Pathology
Abstract

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV1 and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV1 and accelerated decline of FEV1 and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV1 level. Eleven out of 17 SNPs were associated with FEV1 decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD.

Published
2012

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