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Adams RL, McKenna M, Allsopp K, Saleem S, Le Mesurier N, Diar Bakerly N, Turner AM, Gale NK. "I know this is on my chest, let's act": a qualitative study exploring self-management of acute COPD exacerbations with a sputum colour chart to reduce unnecessary antibiotic use. NPJ Prim Care Respir Med 2024; 34:41. [PMID: 39616147 PMCID: PMC11608216 DOI: 10.1038/s41533-024-00398-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/29/2024] [Indexed: 12/06/2024] Open
Abstract
Half of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are caused by bacterial infection, but self-management plans (SMPs) generally advocate use of antibiotics and steroids for all events. We report findings from a qualitative study exploring the acceptability of a sputum colour chart and SMP to guide patient use of antibiotics and steroids (commonly termed a 'rescue pack'). Qualitative interviews were conducted with healthcare professionals (HCPs) and patients from the Colour COPD trial - a randomised controlled trial of usual care (SMP alone) versus usual care plus sputum colour chart to manage AECOPD across England and sampled to promote maximum variation. Interviews were audio-recorded, transcribed clean verbatim, then analysed thematically, using an adapted Framework approach. Expert patients contributed to the patient data analysis. Fourteen HCPs and 39 patients were interviewed from primary and secondary care. Three overarching themes were identified. (1) Handling tensions: the tension between stewardship of antimicrobials and need to reduce risk of serious illness. (2) Clinical and embodied legacies: established clinical practices of infection control and patient's own experiences of managing their condition over time have focused on early intervention for AECOPD. (3) Changing self-management practices: opportunities for changing practices through negotiating change between HCP and patient. In conclusion, while, in principle, the assessment of sputum colour using a chart to manage AECOPD was acceptable to both patients and HCPs, in practice, it is unlikely to have significant impact on well-established clinical practices for infection control and patient habits of self-management.
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Affiliation(s)
- R L Adams
- Health Services Management Centre, School of Social Policy and Society, University of Birmingham, Birmingham, UK
| | - M McKenna
- Health Services Management Centre, School of Social Policy and Society, University of Birmingham, Birmingham, UK
| | - K Allsopp
- Independent Patient/Public Co-analyst, Birmingham, UK
| | - S Saleem
- Independent Patient/Public Co-analyst, Birmingham, UK
- Institute of Education, University College London, London, UK
| | - N Le Mesurier
- Health Services Management Centre, School of Social Policy and Society, University of Birmingham, Birmingham, UK
| | - N Diar Bakerly
- Northern Care Alliance, Salford, UK
- Manchester Metropolitan University, Manchester, UK
| | - A M Turner
- Department of Applied Health Sciences, University of Birmingham, Birmingham, UK
| | - N K Gale
- Health Services Management Centre, School of Social Policy and Society, University of Birmingham, Birmingham, UK.
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Enríquez-Rodríguez CJ, Pascual-Guardia S, Casadevall C, Caguana-Vélez OA, Rodríguez-Chiaradia D, Barreiro E, Gea J. Proteomic Blood Profiles Obtained by Totally Blind Biological Clustering in Stable and Exacerbated COPD Patients. Cells 2024; 13:866. [PMID: 38786086 PMCID: PMC11119172 DOI: 10.3390/cells13100866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
Although Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent, it is often underdiagnosed. One of the main characteristics of this heterogeneous disease is the presence of periods of acute clinical impairment (exacerbations). Obtaining blood biomarkers for either COPD as a chronic entity or its exacerbations (AECOPD) will be particularly useful for the clinical management of patients. However, most of the earlier studies have been characterized by potential biases derived from pre-existing hypotheses in one or more of their analysis steps: some studies have only targeted molecules already suggested by pre-existing knowledge, and others had initially carried out a blind search but later compared the detected biomarkers among well-predefined clinical groups. We hypothesized that a clinically blind cluster analysis on the results of a non-hypothesis-driven wide proteomic search would determine an unbiased grouping of patients, potentially reflecting their endotypes and/or clinical characteristics. To check this hypothesis, we included the plasma samples from 24 clinically stable COPD patients, 10 additional patients with AECOPD, and 10 healthy controls. The samples were analyzed through label-free liquid chromatography/tandem mass spectrometry. Subsequently, the Scikit-learn machine learning module and K-means were used for clustering the individuals based solely on their proteomic profiles. The obtained clusters were confronted with clinical groups only at the end of the entire procedure. Although our clusters were unable to differentiate stable COPD patients from healthy individuals, they segregated those patients with AECOPD from the patients in stable conditions (sensitivity 80%, specificity 79%, and global accuracy, 79.4%). Moreover, the proteins involved in the blind grouping process to identify AECOPD were associated with five biological processes: inflammation, humoral immune response, blood coagulation, modulation of lipid metabolism, and complement system pathways. Even though the present results merit an external validation, our results suggest that the present blinded approach may be useful to segregate AECOPD from stability in both the clinical setting and trials, favoring more personalized medicine and clinical research.
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Affiliation(s)
- Cesar Jessé Enríquez-Rodríguez
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Sergi Pascual-Guardia
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Carme Casadevall
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Oswaldo Antonio Caguana-Vélez
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Diego Rodríguez-Chiaradia
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Esther Barreiro
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
| | - Joaquim Gea
- Respiratory Medicine Department, Hospital del Mar—IMIM, 08003 Barcelona, Spain; (C.J.E.-R.); (S.P.-G.); (C.C.); (O.A.C.-V.); (D.R.-C.); (E.B.)
- MELIS Department, Universitat Pompeu Fabra, 08003 Barcelona, Spain
- CIBERES, ISCiii, 08003 Barcelona, Spain
- BRN, 08003 Barcelona, Spain
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Takada K, Suzukawa M, Tashimo H, Ohshima N, Fukutomi Y, Kobayashi N, Taniguchi M, Ishii M, Akishita M, Ohta K. Serum MMP3 and IL1-RA levels may be useful biomarkers for detecting asthma and chronic obstructive pulmonary disease overlap in patients with asthma. World Allergy Organ J 2023; 16:100840. [PMID: 38020287 PMCID: PMC10663683 DOI: 10.1016/j.waojou.2023.100840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 08/16/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
Background Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them. Objective To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients. Methods This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed. Results Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age. Conclusion MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma.
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Affiliation(s)
- Kazufumi Takada
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
- Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Maho Suzukawa
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Hiroyuki Tashimo
- Asthma, Allergy and Rheumatology Center, National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Nobuharu Ohshima
- Department of Respiratory Medicine, National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
| | - Yuma Fukutomi
- Clinical Research Center, National Hospital Organization Sagamihara National Hospital, Kanagawa, 252-0392, Japan
| | | | - Masami Taniguchi
- Clinical Research Center, National Hospital Organization Sagamihara National Hospital, Kanagawa, 252-0392, Japan
- Shonan Kamakura General Hospital, Kanagawa, 247-8533, Japan
| | - Masaki Ishii
- Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Masahiro Akishita
- Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Ken Ohta
- Clinical Research Center, National Hospital Organization Tokyo National Hospital, Tokyo, 204-8585, Japan
- Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, Tokyo, 204-8522, Japan
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Park SC, Saiphoklang N, Phillips J, Wilgus ML, Buhr RG, Tashkin DP, Cooper CB, Barjaktarevic I. Three-Month Variability of Commonly Evaluated Biomarkers in Clinically Stable COPD. Int J Chron Obstruct Pulmon Dis 2023; 18:1475-1486. [PMID: 37485051 PMCID: PMC10362903 DOI: 10.2147/copd.s396549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/06/2023] [Indexed: 07/25/2023] Open
Abstract
Introduction Clinical decisions in chronic obstructive pulmonary disease (COPD) treatment often utilize serially assessed physiologic parameters and biomarkers. To better understand the reliability of these tests, we evaluated changes in commonly assessed biomarkers over 3 months in patients with clinically stable COPD. Methods We performed an observational prospective cohort study of 89 individuals with clinically stable COPD, defined as no exacerbation history within 3 months of enrollment. Biomarkers included lung function and functional performance status, patient-reported outcomes of symptoms and health status, and blood markers of inflammation. The correlation between testing at baseline and at 3-month follow-up was reported as the intraclass correlation coefficient (ICC). "Outliers" had significant variability between tests, defined as >1.645 standard deviations between the two measurements. Differences in clinical features between outliers and others were compared. Results Participants with COPD (n = 89) were 70.5 ± 6.7 years old, 54 (61%) male, had a 40 pack-year smoking history with 24.7% being current smokers, and postbronchodilator forced expiratory volume in one second (FEV1) 62.3 ± 22.7% predicted. The biomarkers with excellent agreement between the initial and the follow-up measurements were FEV1 (ICC = 0.96), Saint George's Respiratory Questionnaire (SGRQ) (ICC = 0.98), COPD Assessment Test (CAT) (ICC = 0.93) and C-reactive protein (CRP) (ICC = 0.90). By contrast, parameters showing less robust agreement were 6-minute walking distance (ICC = 0.75), eosinophil count (ICC = 0.77), erythrocyte sedimentation rate (ICC = 0.75) and white blood cell count (ICC = 0.48). Individuals with greater variability in biomarkers reported chronic bronchitis more often and had higher baseline SGRQ and CAT scores. Conclusion Our study evaluated the stability of commonly assessed biomarkers in clinically stable COPD and showed excellent agreement between baseline and three-month follow-up values for FEV1, SGRQ, CAT and CRP. Individuals with chronic bronchitis and more symptomatic disease at baseline demonstrated greater variability in 3-month interval biomarkers.
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Affiliation(s)
- Seon Cheol Park
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Division of Pulmonology, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Narongkorn Saiphoklang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Thammasat University, Pathum Thani, Thailand
| | | | - May-Lin Wilgus
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Russell G Buhr
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Donald P Tashkin
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Christopher B Cooper
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Exercise Physiology Research Laboratory, Department of Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Igor Barjaktarevic
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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5
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Uysal P. Novel Applications of Biomarkers in Chronic Obstructive Pulmonary Disease. Biomark Med 2022. [DOI: 10.2174/9789815040463122010017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is an important health
problem and an increasing cause of morbidity and mortality worldwide. Currently,
COPD is considered a multisystem disease. Although it primarily affects the lungs,
structural and functional changes occur in other organs due to systemic inflammation.
It is stated that in patients with COPD, airway and systemic inflammatory markers are
increased and that these markers are high are associated with a faster decline in lung
functions. In recent years, numerous articles have been published on the discovery and
evaluation of biomarkers in COPD. Many markers have also been studied to accurately
assess COPD exacerbations and provide effective treatment. However, based on the
evidence from published studies, a single molecule has not been adequately validated
for broad clinical use.
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Affiliation(s)
- Pelin Uysal
- Department of Chest Diseases, Faculty of Medicine, Mehmet Ali Aydınlar University, Atakent
Hospital, Istanbul, Turkey
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6
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Asadi Jozani K, Kouthouridis S, Hirota JA, Zhang B. Next generation preclinical models of lung development, physiology and disease. CAN J CHEM ENG 2022. [DOI: 10.1002/cjce.24581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Kimia Asadi Jozani
- School of Biomedical Engineering, McMaster University 1280 Main Street West, Hamilton Ontario Canada
| | - Sonya Kouthouridis
- Department of Chemical Engineering McMaster University Hamilton Ontario Canada
| | - Jeremy Alexander Hirota
- School of Biomedical Engineering, McMaster University 1280 Main Street West, Hamilton Ontario Canada
- Department of Medicine, Division of Respirology McMaster University Hamilton Ontario Canada
- Firestone Institute for Respiratory Health St. Joseph’s Hospital, Hamilton Ontario Canada
| | - Boyang Zhang
- School of Biomedical Engineering, McMaster University 1280 Main Street West, Hamilton Ontario Canada
- Department of Chemical Engineering McMaster University Hamilton Ontario Canada
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Abstract
Over the last 20 years, it has become possible to use a precision medicine approach to the management of chronic obstructive pulmonary disease (COPD). Clinical and physiological features as well as a blood biomarker can be used to target treatments to patients most likely to benefit and avoid treatment in patients less likely to benefit. Future advances in a precision medicine approach to COPD will depend on more precise characterization of individual patients, possibly using quantitative imaging, new physiological techniques, novel biomarkers and genetic profiling. Precision medicine has led to significant improvements in the management of COPD and clinicians should use all available information to optimize the treatment of individual patients.
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Effah CY, Drokow EK, Agboyibor C, Ding L, He S, Liu S, Akorli SY, Nuamah E, Sun T, Zhou X, Liu H, Xu Z, Feng F, Wu Y, Zhang X. Neutrophil-Dependent Immunity During Pulmonary Infections and Inflammations. Front Immunol 2021; 12:689866. [PMID: 34737734 PMCID: PMC8560714 DOI: 10.3389/fimmu.2021.689866] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/23/2021] [Indexed: 01/08/2023] Open
Abstract
Rapid recruitment of neutrophils to an inflamed site is one of the hallmarks of an effective host defense mechanism. The main pathway through which this happens is by the innate immune response. Neutrophils, which play an important part in innate immune defense, migrate into lungs through the modulation actions of chemokines to execute a variety of pro-inflammatory functions. Despite the importance of chemokines in host immunity, little has been discussed on their roles in host immunity. A holistic understanding of neutrophil recruitment, pattern recognition pathways, the roles of chemokines and the pathophysiological roles of neutrophils in host immunity may allow for new approaches in the treatment of infectious and inflammatory disease of the lung. Herein, this review aims at highlighting some of the developments in lung neutrophil-immunity by focusing on the functions and roles of CXC/CC chemokines and pattern recognition receptors in neutrophil immunity during pulmonary inflammations. The pathophysiological roles of neutrophils in COVID-19 and thromboembolism have also been summarized. We finally summarized various neutrophil biomarkers that can be utilized as prognostic molecules in pulmonary inflammations and discussed various neutrophil-targeted therapies for neutrophil-driven pulmonary inflammatory diseases.
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Affiliation(s)
| | - Emmanuel Kwateng Drokow
- Department of Radiation Oncology, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou, China
| | - Clement Agboyibor
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Lihua Ding
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Sitian He
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Shaohua Liu
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Senyo Yao Akorli
- College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Emmanuel Nuamah
- College of Agriculture and Natural Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Tongwen Sun
- General ICU, Henan Key Laboratory of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaolei Zhou
- Department of Respiratory, Henan Provincial Chest Hospital, Zhengzhou, China
| | - Hong Liu
- Department of Respiratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhiwei Xu
- Department of Respiratory and Critical Care Medicine, People’s Hospital of Zhengzhou University & Henan Provincial People’s Hospital, Zhengzhou, China
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Yongjun Wu
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xiaoju Zhang
- Department of Respiratory and Critical Care Medicine, People’s Hospital of Zhengzhou University & Henan Provincial People’s Hospital, Zhengzhou, China
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Egervall K, Rosso A, Elmståhl S. Association between cardiovascular disease- and inflammation-related serum biomarkers and poor lung function in elderly. Clin Proteomics 2021; 18:23. [PMID: 34583636 PMCID: PMC8480099 DOI: 10.1186/s12014-021-09329-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/15/2021] [Indexed: 12/14/2022] Open
Abstract
Background Cardiovascular disease (CVD) is a common comorbidity in chronic obstructive pulmonary disease (COPD) and reduced lung function is an important risk factor for CVD and CVD-related death. However, the mechanisms behind the increased risk for CVD in COPD patients are not fully understood. Methods We examined the association between CVD- and inflammation-related serum biomarkers, and pulmonary function in a geriatric population. 266 biomarkers related to CVD and inflammation were analyzed in blood samples from 611 subjects aged 66–86 years who participated in the Good Aging in Skåne study. Serum levels were assessed by a proximity extension assay. Pulmonary function was measured using the lower limit of normality (LLN) spirometry criteria, i.e., forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < LLN. Logistic regression models were implemented and multiple comparisons were accounted for. Results 10.3% of the study participants fulfilled pulmonary function decline criteria according to LLN. Out of the 266 biomarkers, only plasminogen activator, urokinase receptor (PLAUR) was statistically significantly associated with decreased pulmonary function. We could not find a statistically significant association between pulmonary function decline and other biomarkers previously linked to COPD, such as interleukin 6, tumor necrosis factor and surfactant protein D. Conclusion We found that serum levels of PLAUR are associated with pulmonary function decline in older adults. PLAUR is activated following inflammation and promotes matrix metallopeptidase (MMP) activation and extracellular matrix (ECM) degradation. This implies that PLAUR could play a role in the early phase of COPD pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12014-021-09329-7.
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Affiliation(s)
- K Egervall
- Division of Geriatric Medicine, Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden.
| | - A Rosso
- Division of Geriatric Medicine, Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden
| | - S Elmståhl
- Division of Geriatric Medicine, Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden
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10
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Li Q, Wong W, Birnberg A, Chakrabarti A, Yang X, Choy DF, Olsson J, Verschueren E, Neighbors M, Sandoval W, Rosenberger CM, Grimbaldeston MA, Tew GW. Lysophosphatidic acid species are associated with exacerbation in chronic obstructive pulmonary disease. BMC Pulm Med 2021; 21:301. [PMID: 34556083 PMCID: PMC8461999 DOI: 10.1186/s12890-021-01670-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 09/16/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) exacerbations are heterogenous and profoundly impact the disease trajectory. Bioactive lipid lysophosphatidic acid (LPA) has been implicated in airway inflammation but the significance of LPA in COPD exacerbation is not known. The aim of the study was to investigate the utility of serum LPA species (LPA16:0, 18:0, 18:1, 18:2, 20:4) as biomarkers of COPD exacerbation. PATIENTS AND METHODS LPA species were measured in the baseline placebo sera of a COPD randomized controlled trial. Tertile levels of each LPA were used to assign patients into biomarker high, medium, and low subgroups. Exacerbation rate and risk were compared among the LPA subgroups. RESULTS The levels of LPA species were intercorrelated (rho 0.29-0.91). Patients with low and medium levels of LPA (LPA16:0, 20:4) had significantly higher exacerbation rate compared to the respective LPA-high patients [estimated rate per patient per year (95% CI)]: LPA16:0-low = 1.2 (0.8-1.9) (p = 0.019), LPA16:0-medium = 1.3 (0.8-2.0) (p = 0.013), LPA16:0-high = 0.5 (0.2-0.9); LPA20:4-low = 1.4 (0.9-2.1) (p = 0.0033), LPA20:4-medium = 1.2 (0.8-1.8) (p = 0.0089), LPA20:4-high = 0.4 (0.2-0.8). These patients also had earlier time to first exacerbation (hazard ratio (95% CI): LPA16:0-low = 2.6 (1.1-6.0) (p = 0.028), LPA16:0-medium = 2.7 (1.2-6.3) (p = 0.020); LPA20.4-low = 2.8 (1.2-6.6) (p = 0.017), LPA20:4-medium = 2.7 (1.2-6.4) (p = 0.021). Accordingly, these patients had a significant increased exacerbation risk compared to the respective LPA-high subgroups [odd ratio (95% CI)]: LPA16:0-low = 3.1 (1.1-8.8) (p = 0.030), LPA16:0-medium = 3.0 (1.1-8.3) (p = 0.031); LPA20:4-low = 3.8 (1.3-10.9) (p = 0.012), LPA20:4-medium = 3.3 (1.2-9.5) (p = 0.025). For the other LPA species (LPA18:0, 18:1, 18:2), the results were mixed; patients with low and medium levels of LPA18:0 and 18:2 had increased exacerbation rate, but only LPA18:0-low patients had significant increase in exacerbation risk and earlier time to first exacerbation compared to the LPA18:0-high subgroup. CONCLUSIONS The study provided evidence of association between systemic LPA levels and exacerbation in COPD. Patients with low and medium levels of specific LPA species (LPA16:0, 20:4) had increased exacerbation rate, risk, and earlier time to first exacerbation. These non-invasive biomarkers may aid in identifying high risk patients with dysregulated LPA pathway to inform risk management and drug development.
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Affiliation(s)
- Qingling Li
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Weng Wong
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Andrew Birnberg
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Arindam Chakrabarti
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | - Xiaoying Yang
- Department of Biostatistics, Genentech, Inc., South San Francisco, CA, USA
| | - David F Choy
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | - Julie Olsson
- Product Development Immunology, Infectious Disease and Ophthalmology, Genentech, Inc., South San Francisco, CA, USA
| | - Erik Verschueren
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Margaret Neighbors
- OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, USA
| | - Wendy Sandoval
- Department of Microchemistry, Proteomics and Lipidomics, Genentech, Inc., South San Francisco, CA, USA
| | - Carrie M Rosenberger
- Department of Biomarker Discovery OMNI, Genentech, Inc., South San Francisco, CA, USA
| | | | - Gaik W Tew
- Product Development Immunology, Infectious Disease and Ophthalmology, Genentech, Inc., South San Francisco, CA, USA.
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11
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Jenkins CR. Towards precision in defining COPD exacerbations. Breathe (Sheff) 2021; 17:210081. [PMID: 35035551 PMCID: PMC8753624 DOI: 10.1183/20734735.0081-2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/28/2021] [Indexed: 11/25/2022] Open
Abstract
COPD is the most prevalent chronic respiratory disease worldwide and a major cause of disability and death. Acute exacerbations of COPD remain a key feature of the disease in many patients and research assessing interventions to prevent and treat them requires a robust definition with high sensitivity and specificity. To date, no such definition exists, and multiple different definitions are used in clinical studies depending on the research question. The strengths and weaknesses of current definitions are discussed in the context of evolving knowledge and different settings in which studies are undertaken. Whether identification and recording of exacerbations remains essentially clinical, or can be identified with a dependable biomarker, it should be sensitive and adaptable to context while retaining clarity and facilitating data collection. This is essential to progress a better understanding of the pathophysiology and phenotypic expression of exacerbations to reduce their impact and personal burden for patients.
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Affiliation(s)
- Christine R. Jenkins
- Respiratory Group, The George Institute for Global Health, Sydney, Australia
- UNSW Sydney, Sydney, Australia
- Concord Clinical School, University of Sydney, Sydney, Australia
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12
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Serban KA, Pratte KA, Bowler RP. Protein Biomarkers for COPD Outcomes. Chest 2021; 159:2244-2253. [PMID: 33434499 PMCID: PMC8213963 DOI: 10.1016/j.chest.2021.01.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 12/14/2020] [Accepted: 01/01/2021] [Indexed: 12/15/2022] Open
Abstract
COPD is a clinically heterogeneous syndrome characterized by injury to airways, airspaces, and lung vasculature and usually caused by tobacco smoke and/or air pollution exposure. COPD is also independently associated with nonpulmonary comorbidities (eg, cardiovascular disease) and malignancies (eg, GI, bladder), suggesting a role for systemic injury. Since not all those with exposure develop COPD, there has been a search for plasma and lung biomarkers that confer increased cross-sectional and longitudinal risk. This search typically focuses on clinically relevant COPD outcomes such as FEV1, FEV1 decline, CT measurements of emphysema, or exacerbation frequency. The rapid advances in omics technology and the molecular phenotyping of COPD cohorts now permit large-scale evaluation of genetic, transcriptomic, proteomic, and metabolic biomarkers. This review focuses on protein biomarkers associated with clinically relevant COPD outcomes. The prototypic COPD protein biomarker is alpha-1 antitrypsin; however, this biomarker only accounts for 1% to 5% of COPD. This article reviews and summarizes the evidence for other validated biomarkers for each COPD outcome, and discusses their advantages, weaknesses, and required regulatory steps to move the biomarker from the bench into clinic. Although we highlight the emergence of many novel biomarkers (eg, fibrinogen, soluble receptor for advanced glycation, surfactant protein D, club cell secretory protein), there is increasing evidence that individual biomarkers only explain a fraction of the increased COPD risk and that multiple biomarker panels are needed to completely explain clinical variation and risk in individuals and populations.
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Affiliation(s)
- Karina A Serban
- National Jewish Health, Denver; University of Colorado, Anschutz Medical Campus, Aurora, CO.
| | | | - Russell P Bowler
- National Jewish Health, Denver; University of Colorado, Anschutz Medical Campus, Aurora, CO
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13
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Singh D, Criner GJ, Dransfield MT, Halpin DMG, Han MK, Lange P, Lettis S, Lipson DA, Mannino D, Martin N, Martinez FJ, Miller BE, Wise R, Zhu CQ, Lomas D. InforMing the PAthway of COPD Treatment (IMPACT) trial: fibrinogen levels predict risk of moderate or severe exacerbations. Respir Res 2021; 22:130. [PMID: 33910578 PMCID: PMC8080358 DOI: 10.1186/s12931-021-01706-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 04/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Fibrinogen is the first qualified prognostic/predictive biomarker for exacerbations in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial investigated fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus FF/VI and UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This analysis used IMPACT trial data to examine the relationship between fibrinogen levels and exacerbation outcomes in patients with COPD. METHODS 8094 patients with a fibrinogen assessment at Week 16 were included, baseline fibrinogen data were not measured. Post hoc analyses were performed by fibrinogen quartiles and by 3.5 g/L threshold. Endpoints included on-treatment exacerbations and adverse events of special interest (AESIs). RESULTS Rates of moderate, moderate/severe, and severe exacerbations were higher in the highest versus lowest fibrinogen quartile (0.75, 0.92 and 0.15 vs 0.67, 0.79 and 0.10, respectively). The rate ratios (95% confidence interval [CI]) for exacerbations in patients with fibrinogen levels ≥ 3.5 g/L versus those with fibrinogen levels < 3.5 g/L were 1.03 (0.95, 1.11) for moderate exacerbations, 1.08 (1.00, 1.15) for moderate/severe exacerbations, and 1.30 (1.10, 1.54) for severe exacerbations. There was an increased risk of moderate/severe exacerbation (hazard ratio [95% CI]: highest vs lowest quartile 1.16 [1.04, 1.228]; ≥ 3.5 g/L vs < 3.5 g/L: 1.09 [1.00, 1.16]) and severe exacerbation (1.35 [1.09, 1.69]; 1.27 [1.08, 1.47], respectively) with increasing fibrinogen level. Cardiovascular AESIs were highest in patients in the highest fibrinogen quartile. CONCLUSIONS Rate and risk of exacerbations was higher in patients with higher fibrinogen levels. This supports the validity of fibrinogen as a predictive biomarker for COPD exacerbations, and highlights the potential use of fibrinogen as an enrichment strategy in trials examining exacerbation outcomes. TRIAL REGISTRATION NCT02164513.
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Affiliation(s)
- Dave Singh
- Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK
| | - Gerard J Criner
- Pulmonary and Critical Care Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Mark T Dransfield
- Division of Pulmonary, Allergy, and Critical Care Medicine, Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David M G Halpin
- University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK
| | - MeiLan K Han
- University of Michigan, Pulmonary & Critical Care, Ann Arbor, MI, USA
| | - Peter Lange
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Sally Lettis
- Biostatistics, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK
| | - David A Lipson
- Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA
- Pulmonary, Allergy and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David Mannino
- University of Kentucky College of Public Health, Lexington, KY, USA
| | - Neil Martin
- Global Medical Affairs, GlaxoSmithKline, Brentford, Middlesex, UK
- Institute for Lung Health, University of Leicester, Leicester, UK
| | | | - Bruce E Miller
- Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA
| | - Robert Wise
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chang-Qing Zhu
- Biostatistics, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK
| | - David Lomas
- Division of Medicine, UCL Respiratory, Rayne Building, University College London, London, WC1E 6BN, UK.
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14
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Fibrinogen is a promising biomarker for chronic obstructive pulmonary disease: evidence from a meta-analysis. Biosci Rep 2021; 40:225825. [PMID: 32677669 PMCID: PMC7383837 DOI: 10.1042/bsr20193542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 07/08/2020] [Accepted: 07/15/2020] [Indexed: 02/08/2023] Open
Abstract
Backgrounds: Some studies have reported association of circulating fibrinogen with the risk of chronic obstructive pulmonary disease (COPD), and the results are conflicting. To yield more information, we aimed to test the hypothesis that circulating fibrinogen is a promising biomarker for COPD by a meta-analysis. Methods: Data extraction and quality assessment were independently completed by two authors. Effect-size estimates are expressed as weighted mean difference (WMD) with 95% confidence interval (95% CI). Results: Forty-five articles involving 5586/18604 COPD patients/controls were incorporated. Overall analyses revealed significantly higher concentrations of circulating fibrinogen in COPD patients than in controls (WMD: 84.67 mg/dl; 95% CI: 64.24–105.10). Subgroup analyses by COPD course showed that the degree of increased circulating fibrinogen in patients with acute exacerbations of COPD (AECOPD) relative to controls (WMD: 182.59 mg/dl; 95% CI: 115.93–249.25) tripled when compared in patients with stable COPD (WMD: 56.12 mg/dl; 95% CI: 34.56–77.67). By COPD severity, there was a graded increase in fibrinogen with the increased severity of COPD relative to controls (Global Initiative for Obstructive Lung Disease (GOLD) I, II, III, and IV: WMD: 13.91, 29.19, 56.81, and 197.42 mg/dl; 95% CI: 7.70–20.11, 17.43–40.94, 39.20–74.41, and −7.88 to 402.73, respectively). There was a low probability of publication bias. Conclusion: Our findings indicate a graded, concentration-dependent, significant relation between higher circulating fibrinogen and more severity of COPD.
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15
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Celli B, Locantore N, Yates JC, Bakke P, Calverley PMA, Crim C, Coxson HO, Lomas DA, MacNee W, Miller BE, Mullerova H, Rennard SI, Silverman EK, Wouters E, Tal-Singer R, Agusti A, Vestbo J. Markers of disease activity in COPD: an 8-year mortality study in the ECLIPSE cohort. Eur Respir J 2021; 57:13993003.01339-2020. [PMID: 33303557 PMCID: PMC7991608 DOI: 10.1183/13993003.01339-2020] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/20/2020] [Indexed: 01/22/2023]
Abstract
Rationale There are no validated measures of disease activity in COPD. Since “active” disease is expected to have worse outcomes (e.g. mortality), we explored potential markers of disease activity in patients enrolled in the ECLIPSE cohort in relation to 8-year all-cause mortality. Methods We investigated 1) how changes in relevant clinical variables over time (1 or 3 years) relate to 8-year mortality; 2) whether these variables inter-relate; and 3) if any clinical, imaging and/or biological marker measured cross-sectionally at baseline relates to any activity component. Results Results showed that 1) after 1 year, hospitalisation for COPD, exacerbation frequency, worsening of body mass index, airflow obstruction, dyspnoea and exercise (BODE) index or health status (St George's Respiratory Questionnaire (SGRQ)) and persistence of systemic inflammation were significantly associated with 8-year mortality; 2) at 3 years, the same markers, plus forced expiratory volume in 1 s (FEV1) decline and to a lesser degree computed tomography (CT) emphysema, showed association, thus qualifying as markers of disease activity; 3) changes in FEV1, inflammatory cytokines and CT emphysema were not inter-related, while the multidimensional indices (BODE and SGRQ) showed modest correlations; and 4) changes in these markers could not be predicted by any baseline cross-sectional measure. Conclusions In COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores and FEV1 decline are independent markers of disease activity associated with 8-year all-cause mortality. These disease activity markers are generally independent and not predictable from baseline measurements. In patients with COPD, 1- and 3-year changes in exacerbation frequency, systemic inflammation, BODE and SGRQ scores, and FEV1 decline, are independent markers of disease activity associated with 8-year all-cause mortalityhttps://bit.ly/2CyifcN
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Affiliation(s)
- Bartolome Celli
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Joint first authors
| | | | | | - Per Bakke
- Institute of Internal Medicine, University of Bergen, Bergen, Norway
| | - Peter M A Calverley
- Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | | | - Harvey O Coxson
- Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada
| | - David A Lomas
- UCL Respiratory, Rayne Institute, University College London, London, UK
| | | | | | | | | | - Edwin K Silverman
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Emiel Wouters
- University of Maastricht, Maastricht, The Netherlands.,Ludwig Boltzmann Institute for Lung Health, Vienna, Austria
| | | | - Alvar Agusti
- Respiratory Institute, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.,CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Joint senior authors
| | - Jørgen Vestbo
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK.,Joint senior authors
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16
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Crapo J, Gupta A, Lynch DA, Vogel-Claussen J, Watz H, Turner AM, Mroz RM, Janssens W, Ludwig-Sengpiel A, Beck M, Langellier B, Ittrich C, Risse F, Diefenbach C. FOOTPRINTS study protocol: rationale and methodology of a 3-year longitudinal observational study to phenotype patients with COPD. BMJ Open 2021; 11:e042526. [PMID: 33753437 PMCID: PMC7986686 DOI: 10.1136/bmjopen-2020-042526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/01/2020] [Accepted: 02/18/2021] [Indexed: 01/09/2023] Open
Abstract
INTRODUCTION A better understanding is needed of the different phenotypes that exist for patients with chronic obstructive pulmonary disease (COPD), their relationship with the pathogenesis of COPD and how they may affect disease progression. Biomarkers, including those associated with emphysema, may assist in characterising patients and in predicting and monitoring the course of disease. The FOOTPRINTS study (study 352.2069) aims to identify biomarkers associated with emphysema, over a 3-year period. METHODS AND ANALYSIS The FOOTPRINTS study is a prospective, longitudinal, multinational (12 countries), multicentre (51 sites) biomarker study, which has enrolled a total of 463 ex-smokers, including subjects without airflow limitation (as defined by the 2015 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report), patients with COPD across the GOLD stages 1-3 and patients with COPD and alpha1-antitrypsin deficiency. The study has an observational period lasting 156 weeks that includes seven site visits and additional phone interviews. Biomarkers in blood and sputum, imaging data (CT and magnetic resonance), clinical parameters, medical events of special interest and safety are being assessed at regular visits. Disease progression based on biomarker values and COPD phenotypes are being assessed using multivariate statistical prediction models. ETHICS AND DISSEMINATION The study protocol was approved by the authorities and ethics committees/institutional review boards of the respective institutions where applicable, which included study sites in Belgium, Canada, Denmark, Finland, Germany, Japan, Korea, Poland, Spain, Sweden, UK and USA; written informed consent has been obtained from all study participants. Ethics committee approval was obtained for all participating sites prior to enrolment of the study participants. The study results will be reported in peer-reviewed publications. TRIAL REGISTRATION NUMBER NCT02719184.
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Affiliation(s)
- James Crapo
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
| | - Abhya Gupta
- TA Inflammation Med, Boehringer Ingelheim International GmbH, Biberach an der Riss, Germany
| | - David A Lynch
- Department of Radiology, National Jewish Health, Denver, Colorado, USA
| | - Jens Vogel-Claussen
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
- Biomedical research in endstage and obstructive lung disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Henrik Watz
- Pulmonary Research Institute, LungenClinic Grosshansdorf, Grosshansdorf, Germany
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany
| | - Alice M Turner
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Robert M Mroz
- 2nd Department of Lung Diseases and Tuberculosis, Bialystok Medical University, Bialystok, Poland
| | - Wim Janssens
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Laboratory of Respiratory Diseases and Thoracic surgery (BREATH), University Hospital Leuven, KU Leuven, Belgium
| | | | - Markus Beck
- Department of Clinical Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | | | - Carina Ittrich
- Global Department of Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Frank Risse
- Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Claudia Diefenbach
- Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
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17
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Karakioulaki M, Papakonstantinou E, Stolz D. Extracellular matrix remodelling in COPD. Eur Respir Rev 2020; 29:29/158/190124. [PMID: 33208482 DOI: 10.1183/16000617.0124-2019] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 05/16/2020] [Indexed: 12/30/2022] Open
Abstract
The extracellular matrix (ECM) of the lung plays several important roles in lung function, as it offers a low resistant pathway that allows the exchange of gases, provides compressive strength and elasticity that supports the fragile alveolar-capillary intersection, controls the binding of cells with growth factors and cell surface receptors and acts as a buffer against retention of water.COPD is a chronic inflammatory respiratory condition, characterised by various conditions that result in progressive airflow limitation. At any stage in the course of the disease, acute exacerbations of COPD may occur and lead to accelerated deterioration of pulmonary function. A key factor of COPD is airway remodelling, which refers to the serious alterations of the ECM affecting airway wall thickness, resistance and elasticity. Various studies have shown that serum biomarkers of ECM turnover are significantly associated with disease severity in patients with COPD and may serve as potential targets to control airway inflammation and remodelling in COPD. Unravelling the complete molecular composition of the ECM in the diseased lungs will help to identify novel biomarkers for disease progression and therapy.
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Affiliation(s)
- Meropi Karakioulaki
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland
| | - Eleni Papakonstantinou
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland.,Dept of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Daiana Stolz
- Clinic of Pulmonary Medicine and Respiratory Cell Research, University Hospital, Basel, Switzerland
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18
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Liu D, Meister M, Zhang S, Vong CI, Wang S, Fang R, Li L, Wang PG, Massion P, Ji X. Identification of lipid biomarker from serum in patients with chronic obstructive pulmonary disease. Respir Res 2020; 21:242. [PMID: 32957957 PMCID: PMC7507726 DOI: 10.1186/s12931-020-01507-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States with no effective treatment. The current diagnostic method, spirometry, does not accurately reflect the severity of COPD disease status. Therefore, there is a pressing unmet medical need to develop noninvasive methods and reliable biomarkers to detect early stages of COPD. Lipids are the fundamental components of cell membranes, and dysregulation of lipids was proven to be associated with COPD. Lipidomics is a comprehensive approach to all the pathways and networks of cellular lipids in biological systems. It is widely used for disease diagnosis, biomarker identification, and pathology disorders detection relating to lipid metabolism. METHODS In the current study, a total of 25 serum samples were collected from 5 normal control subjects and 20 patients with different stages of COPD according to the global initiative for chronic obstructive lung disease (GOLD) (GOLD stages I ~ IV, 5 patients per group). After metabolite extraction, lipidomic analysis was performed using electrospray ionization mass spectrometry (ESI-MS) to detect the serum lipid species. Later, the comparisons of individual lipids were performed between controls and patients with COPD. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) analysis were utilized to test the potential biomarkers. Finally, correlations between the validated lipidomic biomarkers and disease stages, age, FEV1% pack years and BMI were evaluated. RESULTS Our results indicate that a panel of 50 lipid metabolites including phospholipids, sphingolipids, glycerolipids, and cholesterol esters can be used to differentiate the presence of COPD. Among them, 10 individual lipid species showed significance (p < 0.05) with a two-fold change. In addition, lipid ratios between every two lipid species were also evaluated as potential biomarkers. Further multivariate data analysis and receiver operating characteristic (ROC: 0.83 ~ 0.99) analysis suggest that four lipid species (AUC:0.86 ~ 0.95) and ten lipid ratios could be potential biomarkers for COPD (AUC:0.94 ~ 1) with higher sensitivity and specificity. Further correlation analyses indicate these potential biomarkers were not affected age, BMI, stages and FEV1%, but were associated with smoking pack years. CONCLUSION Using lipidomics and statistical methods, we identified unique lipid signatures as potential biomarkers for diagnosis of COPD. Further validation studies of these potential biomarkers with large population may elucidate their roles in the development of COPD.
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Affiliation(s)
- Ding Liu
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Maureen Meister
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
- Department of Nutrition, Georgia State University, Atlanta, 30302, USA
| | - Shiying Zhang
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Chi-In Vong
- Department of Nutrition, Georgia State University, Atlanta, 30302, USA
| | - Shuaishuai Wang
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Ruixie Fang
- Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, 30302, USA
| | - Lei Li
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Peng George Wang
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA
| | - Pierre Massion
- Cancer Early Detection and Prevention Initiative, Vanderbilt Ingram Cancer Center; Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Xiangming Ji
- Department of Chemistry, Georgia State University, Atlanta, GA, 30303, USA.
- Department of Nutrition, Georgia State University, Atlanta, 30302, USA.
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Ambient particulate matter attenuates Sirtuin1 and augments SREBP1-PIR axis to induce human pulmonary fibroblast inflammation: molecular mechanism of microenvironment associated with COPD. Aging (Albany NY) 2020; 11:4654-4671. [PMID: 31299012 PMCID: PMC6660058 DOI: 10.18632/aging.102077] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 06/04/2019] [Indexed: 02/07/2023]
Abstract
Evidences have shown a strong link between particulate matter (PM) and increased risk in human mortality and morbidity, including asthma, chronic obstructive pulmonary disease (COPD), respiratory infection, and lung cancer. However, the underlying toxicologic mechanisms remain largely unknown. Utilizing PM-treated human pulmonary fibroblasts (HPF) models, we analyzed gene expression microarray data and Ingenuity Pathway Analysis (IPA) to identify that the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was the main downstream regulator of Sirtuin1 (SIRT1). Quantitative PCR and western blot results showed that SIRT1 inhibited SREBP1 and further downregulated Pirin (PIR) and Nod-like receptor protein 3 (NLRP3) inflammasome after PM exposure. Inhibitors of SIRT1, SREBP1, and PIR could reverse PM-induced inflammation. An in silico analysis revealed that PIR correlated with smoke exposure and early COPD. Immunohistochemical analysis of tissue microarrays from PM-fed mouse models was used to determine the association of PIR with PM. These data demonstrate that the SIRT1-SREBP1-PIR/ NLRP3 inflammasome axis may be associated with PM-induced adverse health issues. SIRT1 functions as a protector from PM exposure, whereas PIR acts as a predictor of PM-induced pulmonary disease. The SIRT1-SREBP1-PIR/ NLRP3 inflammasome axis may present several potential therapeutic targets for PM-related adverse health events.
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20
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Kokelj S, Kim JL, Andersson M, Runström Eden G, Bake B, Olin AC. Intra-individual variation of particles in exhaled air and of the contents of Surfactant protein A and albumin. PLoS One 2020; 15:e0227980. [PMID: 31978133 PMCID: PMC6980535 DOI: 10.1371/journal.pone.0227980] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/04/2020] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Particles in exhaled air (PEx) provide samples of respiratory tract lining fluid from small airways containing, for example, Surfactant protein A (SP-A) and albumin, potential biomarkers of small airway disease. We hypothesized that there are differences between morning, noon, and afternoon measurements and that the variability of repeated measurements is larger between days than within days. METHODS PEx was obtained in sixteen healthy non-smoking adults on 11 occasions, within one day and between days. SP-A and albumin were quantified by ELISA. The coefficient of repeatability (CR), intraclass correlation coefficient (ICC), and coefficient of variation (CV) were used to assess the variation of repeated measurements. RESULTS SP-A and albumin increased significantly from morning towards the noon and afternoon by 13% and 25% on average, respectively, whereas PEx number concentration and particle mean mass did not differ significantly between the morning, noon and afternoon. Between-day CRs were not larger than within-day CRs. CONCLUSIONS Time of the day influences the contents of SP-A and albumin in exhaled particles. The variation of repeated measurements was rather high but was not influenced by the time intervals between measurements.
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Affiliation(s)
- Spela Kokelj
- Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- * E-mail:
| | - Jeong-Lim Kim
- Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marianne Andersson
- Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Gunilla Runström Eden
- Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Björn Bake
- Unit of Respiratory Medicine and Allergy, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anna-Carin Olin
- Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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21
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Benam KH, Novak R, Ferrante TC, Choe Y, Ingber DE. Biomimetic smoking robot for in vitro inhalation exposure compatible with microfluidic organ chips. Nat Protoc 2020; 15:183-206. [PMID: 31925401 DOI: 10.1038/s41596-019-0230-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 07/24/2019] [Indexed: 01/22/2023]
Abstract
Exposure of lung tissues to cigarette smoke is a major cause of human disease and death worldwide. Unfortunately, adequate model systems that can reliably recapitulate disease biogenesis in vitro, including exposure of the human lung airway to fresh whole cigarette smoke (WCS) under physiological breathing airflow, are lacking. This protocol extension builds upon, and can be used with, our earlier protocol for microfabrication of human organs-on-chips. Here, we describe the engineering, assembly and operation of a microfluidically coupled, multi-compartment platform that bidirectionally 'breathes' WCS through microchannels of a human lung small airway microfluidic culture device, mimicking how lung cells may experience smoke in vivo. Several WCS-exposure systems have been developed, but they introduce smoke directly from above the cell cultures, rather than tangentially as naturally occurs in the lung due to lateral airflow. We detail the development of an organ chip-compatible microrespirator and a smoke machine to simulate breathing behavior and smoking topography parameters such as puff time, inter-puff interval and puffs per cigarette. Detailed design files, assembly instructions and control software are provided. This novel platform can be fabricated and assembled in days and can be used repeatedly. Moderate to advanced engineering and programming skills are required to successfully implement this protocol. When coupled with the small airway chip, this protocol can enable prediction of patient-specific biological responses in a matched-comparative manner. We also demonstrate how to adapt the protocol to expose living ciliated airway epithelial cells to smoke generated by electronic cigarettes (e-cigarettes) on-chip.
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Affiliation(s)
- Kambez H Benam
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.,Division of Pulmonary Sciences and Critical Care Medicine, Departments of Medicine and Bioengineering, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Richard Novak
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Thomas C Ferrante
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Youngjae Choe
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Donald E Ingber
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. .,Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA, USA. .,Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
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22
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Keene JD, Jacobson S, Kechris K, Kinney GL, Foreman MG, Doerschuk CM, Make BJ, Curtis JL, Rennard SI, Barr RG, Bleecker ER, Kanner RE, Kleerup EC, Hansel NN, Woodruff PG, Han MK, Paine R, Martinez FJ, Bowler RP, O’Neal WK, Alexis NE, Anderson WH, Barr RG, Bleecker ER, Boucher RC, Bowler RP, Carretta EE, Christenson SA, Comellas AP, Cooper CB, Couper DJ, Criner GJ, Crystal RG, Curtis JL, Doerschuk CM, Dransfield MT, Freeman CM, Han MK, Hansel NN, Hastie AT, Hoffman EA, Kaner RJ, Kanner RE, Kleerup EC, Krishnan JA, LaVange LM, Lazarus SC, Martinez FJ, Meyers DA, Newell JD, Oelsner EC, O’Neal WK, Paine R, Putcha N, Rennard SI, Tashkin DP, Beth Scholand M, Wells JM, Wise RA, Woodruff PG. Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med 2020. [DOI: 10.1164/rccm.201607-1330oc.201.1.test] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Jason D. Keene
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | - Katerina Kechris
- Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Gregory L. Kinney
- Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | - Claire M. Doerschuk
- Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | - Jeffrey L. Curtis
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
- VA Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Stephen I. Rennard
- Division of Pulmonary and Critical Care Medicine, University of Nebraska, Omaha, Nebraska
| | - R. Graham Barr
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Eugene R. Bleecker
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Richard E. Kanner
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah
| | - Eric C. Kleerup
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Nadia N. Hansel
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Prescott G. Woodruff
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, School of Medicine, San Francisco, California; and
| | - MeiLan K. Han
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Robert Paine
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah
| | - Fernando J. Martinez
- Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York
| | | | - Wanda K. O’Neal
- Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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23
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Oshagbemi OA, Franssen FME, Wouters EFM, Maitland-van der Zee AH, Driessen JHM, de Boer A, de Vries F. C-reactive protein as a biomarker of response to inhaled corticosteroids among patients with COPD. Pulm Pharmacol Ther 2019; 60:101870. [PMID: 31785343 DOI: 10.1016/j.pupt.2019.101870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/13/2019] [Accepted: 11/25/2019] [Indexed: 11/30/2022]
Abstract
AIMS C-reactive protein (CRP) is an important biomarker in systemic inflammation in COPD; reports have suggested inhaled corticosteroids (ICS) attenuate CRP levels. We evaluated the risk of moderate-to-severe exacerbations, severe exacerbations and all-cause mortality among patients with COPD currently exposed to Inhaled corticosteroids (ICS) stratified by CRP levels compared to never ICS users with low CRP levels. METHODS We included subjects age 40 or more who had a diagnosis of COPD from January 1, 2005 to January 31, 2014 from the UK Clinical Practice Research Datalink (CPRD). ICS exposure was determined time-dependently, as current, recent, past or never users. We evaluated the risk of moderate-to-severe exacerbations, severe exacerbations and all-cause mortality among ICS users stratified by CRP levels. RESULTS 17,722 subjects diagnosed with COPD met the inclusion criteria. Among current or never ICS with elevated CRP levels we found, no significantly reduced risk of moderate-to-severe or severe exacerbations. For patients currently exposed ICS with CRP levels ≥8 mg/L there was no reduced risk of moderate-to-severe exacerbations (adjusted hazard ratio [adj. HR] 0.99; 95% confidence interval [CI] 0.76-1.31) or severe exacerbations (adj.HR 1.52; 95% CI 0.71-3.27). However, we found an increased risk of all-cause mortality among COPD patients with CRP levels ≥8 mg/L irrespective of ICS exposure. CONCLUSION We did not find a reduced risk of moderate and/or severe COPD exacerbations among COPD patients with varying CRP levels currently exposed to ICS. However, low-grade systemic inflammation was associated with all-cause mortality among COPD patients.
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Affiliation(s)
- Olorunfemi A Oshagbemi
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands; CIRO, Horn, the Netherlands; Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands; Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands
| | - Frits M E Franssen
- CIRO, Horn, the Netherlands; Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands
| | - Emiel F M Wouters
- CIRO, Horn, the Netherlands; Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands; Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, the Netherlands
| | - Anke H Maitland-van der Zee
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands; Department of Respiratory Medicine, Academic University Medical Centre, University of Amsterdam (UvA) Amsterdam, the Netherlands
| | - Johanna H M Driessen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands
| | - Anthonius de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands
| | - Frank de Vries
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the Netherlands; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, the Netherlands.
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24
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Stockley RA, Halpin DMG, Celli BR, Singh D. Chronic Obstructive Pulmonary Disease Biomarkers and Their Interpretation. Am J Respir Crit Care Med 2019; 199:1195-1204. [DOI: 10.1164/rccm.201810-1860so] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Robert A. Stockley
- Lung Investigation Unit, Medicine, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - David M. G. Halpin
- Department of Respiratory Medicine, Royal Devon & Exeter Hospital, Exeter, United Kingdom
| | - Bartolome R. Celli
- Pulmonary and Critical Care Department, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and
| | - Dave Singh
- Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Hospital Trust, Manchester, United Kingdom
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25
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Nandy D, Sharma N, Senapati S. Systematic Review and Meta-Analysis Confirms Significant Contribution of Surfactant Protein D in Chronic Obstructive Pulmonary Disease. Front Genet 2019; 10:339. [PMID: 31057601 PMCID: PMC6479180 DOI: 10.3389/fgene.2019.00339] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 03/29/2019] [Indexed: 12/31/2022] Open
Abstract
Background: Surfactant protein D (SFTPD) is a lung specific protein which performs several key regulatory processes to maintain overall lung function. Several infectious and immune mediated diseases have been shown to be associated with SFTPD. Recent findings have suggested the serum concentration of SFTPD can be used as a diagnostic or prognostic marker for chronic obstructive pulmonary disease (COPD) and acute exacerbation COPD (AECOPD). But these findings lack replication studies from different ethnic populations and meta-analysis, to establish SFTPD as reliable diagnostic or prognostic biomarker for COPD and associated conditions. Methods: We performed systematic literature search based on stringent inclusion and exclusion criteria to identify eligible studies to perform a meta-analysis. Our objective was to assess the predictability of serum SFTPD concentration and SFTPD allelic conformation at rs721917 (C > T) with COPD and AECOPD outcome. These variables were compared between COPD and healthy controls, where mean difference (MD), and odds ratio (OR) were calculated to predict the overall effect size. Review manager (RevMan-v5.3) software was used to analyse the data. Results: A total of eight published reports were included in this study. Comparative serum SFTPD concentration data were extracted from six studies and three studies were evaluated for assessment of genetic marker from SFTPD. Our study identified strong association of elevated serum SFTPD with COPD and AECOPD. Significant association of risk was also observed for “T” allele or “TT” genotype of rs721917 from SFTPD with COPD and AECOPD. Conclusion: Serum concentration and alleleic conformation of SFTPD has a significantly high predictive value for COPD and AECOPD. Thus, these can be tested further and could be applied as a predictive or prognostic marker.
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Affiliation(s)
- Debparna Nandy
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Nidhi Sharma
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Sabyasachi Senapati
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
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26
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Celli BR, Anderson JA, Brook R, Calverley P, Cowans NJ, Crim C, Dixon I, Kim V, Martinez FJ, Morris A, Newby DE, Yates J, Vestbo J. Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial. BMJ Open Respir Res 2019; 6:e000431. [PMID: 31258919 PMCID: PMC6561388 DOI: 10.1136/bmjresp-2019-000431] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 03/29/2019] [Indexed: 11/25/2022] Open
Abstract
Rationale Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts. Objectives Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV1) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV1 of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial. Methods Participants were randomised to daily inhalations of placebo, vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF) or their combination (VI 25/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV1 decline (mL/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender. Results Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV1, FEV1 decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF/VI, p<0.01) at 3 months. Conclusions In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV1 decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD. Trial registration number NCT01313676.
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Affiliation(s)
- Bartolome R Celli
- Pulmonary and Critical Care Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Julie A Anderson
- Research & Development, GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK
| | - Robert Brook
- Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Peter Calverley
- Department of Medicine, Clinical Sciences Centre, University of Liverpool, University Hospital Aintree, Liverpool, Liverpool, UK
| | - Nicholas J Cowans
- GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK
- Veramed Ltd, Twickenham, UK
| | - Courtney Crim
- GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA
| | - Ian Dixon
- GlaxoSmithKline Plc Stockley Park, Uxbridge, Middlesex, UK
- Veramed Ltd, Twickenham, UK
| | - Victor Kim
- Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Fernando J Martinez
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine Samuel J Wood Library, New York City, New York, USA
| | - Andrea Morris
- GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA
| | - David E Newby
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Edinburgh, UK
| | - Julie Yates
- GlaxoSmithKline Research Triangle Park, Research Triangle Park, North Carolina, USA
| | - Joergen Vestbo
- Division of Infection, Immunity and Respiratory Medicine and Allergy, Manchester Academic Health Science Centre, The University of Manchester, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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Meneghini A, Koenigkam-Santos M, Pereira M, Tonidandel P, Terra-Filho J, Cunha F, de Menezes M, Vianna E. Biomass smoke COPD has less tomographic abnormalities but worse hypoxemia compared with tobacco COPD. Braz J Med Biol Res 2019; 52:e8233. [PMID: 31038579 PMCID: PMC6487741 DOI: 10.1590/1414-431x20198233] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 02/07/2019] [Indexed: 11/22/2022] Open
Abstract
Special attention has emerged towards biomass smoke-induced chronic obstructive pulmonary disease (COPD), providing new knowledge for prevention and therapeutic approach of non-smoker COPD patients. However, the understanding of biomass smoke COPD is still limited and somewhat controversial. The aim of the present study was to compare COPD exclusively caused by tobacco smoking with COPD exclusively caused by environmental or occupational exposures. For this cross-sectional study, COPD patients were recruited from outpatient clinics and formed two groups: non-smoker COPD group (n=16) with exposure to biomass smoke who did not smoke cigarette and tobacco smoker COPD group (n=15) with people who did not report biomass smoke exposure. Subjects underwent pulmonary function tests, thoracic high-resolution computed tomography, 6-min walk test, and sputum induction. The non-smoker COPD group had biomass smoke exposure of 133.3±86 hour-years. The tobacco COPD group smoked 48.5±27.4 pack-years. Women were 62.5 and 66.7%, respectively, of non-smokers and smokers. The non-smoker COPD group showed higher prevalence of dyspnea, lower arterial oxygen tension (PaO2), and lower arterial oxygen saturation (SaO2%) with similar spirometry results, lung volumes, and diffusion capacity. Regarding inflammatory biomarkers, differences were detected in sputum number of lymphomononuclear cells and in sputum concentrations of interleukin (IL)-6 and IL-8 with higher values in the smoker group. Emphysema was more prevalent in the tobacco smoker group, which also showed higher relative bronchial wall thickness and lower lung density by quantitative analysis. Biomass smoke induced more hypoxemia compared to tobacco in COPD patients with similar severity.
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Affiliation(s)
- A.C. Meneghini
- Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - M. Koenigkam-Santos
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - M.C. Pereira
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - P.R. Tonidandel
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
| | - J. Terra-Filho
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - F.Q. Cunha
- Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - M.B. de Menezes
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - E.O. Vianna
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Böcskei RM, Benczúr B, Losonczy G, Illyés M, Cziráki A, Müller V, Bohács A, Bikov A. Soluble Urokinase-Type Plasminogen Activator Receptor and Arterial Stiffness in Patients with COPD. Lung 2019; 197:189-197. [PMID: 30820636 PMCID: PMC6486892 DOI: 10.1007/s00408-019-00211-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/18/2019] [Indexed: 02/01/2023]
Abstract
Introduction Soluble urokinase-type plasminogen activator receptor (suPAR) is upregulated by inflammation and plays a role in the pathogenesis of atherosclerosis. Chronic obstructive pulmonary disease (COPD) is associated with enhanced systemic inflammation and increased risk for atherosclerosis, however, studies analysing the circulating suPAR levels in COPD are contradictory. The aim of the study was to investigate plasma suPAR concentrations together with markers of arterial stiffness in COPD. Materials and Methods Twenty-four patients with COPD and 18 non-COPD, control subjects participated in the study. Plasma suPAR was measured, together with lung volumes, symptom burden, exacerbation history, markers of arterial stiffness and soluble inflammatory biomarkers, such as endothelin-1, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6). Results Plasma suPAR levels were higher in COPD (2.84 ± 0.67 ng/ml vs. 2.41 ± 0.57 ng/ml, p = 0.03) and were related to lung function measured with FEV1 (r = − 0.65, p < 0.01) and symptom burden determined with the modified Medical Research Council questionnaire (r = 0.55, p < 0.05). Plasma suPAR concentrations correlated with various measures of arterial stiffness in all subjects, but only with ejection duration in COPD (r = − 0.44, p = 0.03). Conclusions Plasma suPAR levels are elevated in COPD and relate to arterial stiffness. Our results suggest that suPAR may be a potential link between COPD and atherosclerosis.
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Affiliation(s)
- Renáta M Böcskei
- Department of Pulmonology, Semmelweis University, Diós árok Street. 1/c, Budapest, 1125, Hungary.
| | - Béla Benczúr
- 1st Dept of Internal Medicine (Cardiology/Nephrology), Balassa Janos County Hospital, Béri Balogh Ádám Street 5-7, Szekszárd, 7100, Hungary
| | - György Losonczy
- Department of Pulmonology, Semmelweis University, Diós árok Street. 1/c, Budapest, 1125, Hungary
| | - Miklós Illyés
- Heart Institute, Faculty of Medicine, University of Pécs, Ifjúság Street 13, Pecs, 7624, Hungary
| | - Attila Cziráki
- Heart Institute, Faculty of Medicine, University of Pécs, Ifjúság Street 13, Pecs, 7624, Hungary
| | - Veronika Müller
- Department of Pulmonology, Semmelweis University, Diós árok Street. 1/c, Budapest, 1125, Hungary
| | - Anikó Bohács
- Department of Pulmonology, Semmelweis University, Diós árok Street. 1/c, Budapest, 1125, Hungary
| | - András Bikov
- Department of Pulmonology, Semmelweis University, Diós árok Street. 1/c, Budapest, 1125, Hungary
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Mechanisms of bergenin treatment on chronic bronchitis analyzed by liquid chromatography-tandem mass spectrometry based on metabolomics. Biomed Pharmacother 2019; 109:2270-2277. [DOI: 10.1016/j.biopha.2018.11.119] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/07/2018] [Accepted: 11/25/2018] [Indexed: 12/19/2022] Open
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30
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Oh JY, Lee YS, Min KH, Hur GY, Lee SY, Kang KH, Rhee CK, Park SJ, Shim JJ. Decreased serum club cell secretory protein in asthma and chronic obstructive pulmonary disease overlap: a pilot study. Int J Chron Obstruct Pulmon Dis 2018; 13:3411-3417. [PMID: 30425470 PMCID: PMC6203108 DOI: 10.2147/copd.s174545] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Purpose Improvement in the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO), and identification of biomarkers for phenotype recognition will encourage good patient care by providing optimal therapy. We investigated club cell secretory protein (CC-16), a protective and anti-inflammatory mediator, as a new candidate biomarker for diagnosing ACO. Patients and methods We performed a multicenter cohort study. A total of 107 patients were divided into three groups - asthma, COPD, and ACO - according to the Spanish guidelines algorithm, and enrolled into the study. Serum CC-16 levels were measured using commercial ELISA kits. Results Serum CC-16 levels were the lowest in patients with ACO. Low serum CC-16 levels were a significant marker for the ACO even after adjustment for age, sex, and smoking intensity. Serum CC-16 levels were positively correlated with forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25%-75% of FVC, FEV1/FVC, vital capacity, and diffusing capacity of the lung for carbon monoxide, and were negatively correlated with smoking amount (pack-years), bronchodilator response, fractional residual capacity, residual volume, and number of exacerbations per year. FEV1 and serum CC-16 levels were significantly lower in patients with frequent exacerbations. Conclusion Serum CC-16 has the potential to be a biomarker for ACO diagnosis and also treat frequent exacerbations in patients with chronic inflammatory airway diseases.
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Affiliation(s)
- Jee Youn Oh
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Young Seok Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Kyung Hoon Min
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Gyu Young Hur
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Sung Yong Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Kyung Ho Kang
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
| | - Chin Kook Rhee
- Division of Pulmonary Medicine, Department of Internal Medicine, Catholic University Seoul Hospital, Seoul, Republic of Korea
| | - Seoung Ju Park
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea
| | - Jae Jeong Shim
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea,
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Sanja M, Jozsef P, Sanja PG, Ivana C, Ivana G, Lana G, Gordana S, Renata L, Lepej Snjezana Z. Cytokines and statin therapy in chronic obstructive pulmonary disease patients. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:533-538. [PMID: 30278779 DOI: 10.1080/00365513.2018.1514464] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cytokines are biological response modifiers involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). This study investigated the potential use of cytokines as disease severity biomarkers in COPD patients and the possible effect of statin therapy on cytokine expression. Possible associations between cytokines, body mass index (BMI) and smoking have also been studied. Cytokines IFN-γ, IL-2, IL-12 p70, TNF-α, TNF-β, IL-4, IL-5, IL-6, IL-10, IL-1β and IL-8 were measured in the plasma of 100 clinically stable COPD patients using a fluorescent bead immunoassay on a flow cytometer. When patients were grouped according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (A-D), no significant differences in cytokine concentrations were found (p > .05). Significantly decreased concentrations of IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12p70 and TNF-α were found in COPD patients receiving statin therapy in comparison with COPD patients not receiving statin therapy (p < .05). COPD patients with increased BMI (>25) had decreased IL-2 (p=.038), IL-8 (p = .039) and IL-10 (p = .005) concentrations compared to normal BMI (20-25) patients. Current COPD smokers had increased concentrations of IL-5 (p = .037) compared to former COPD smokers. Hierarchical cluster analysis showed several patterns of measured cytokines in serum of patients with stable COPD. Statin therapy is associated with decreased expression of selected Th1 and Th2 cytokines in COPD, and this effect could be of relevance in COPD patients with increased cardiovascular risk. Concentrations of Th1 and Th2 cytokines in plasma cannot be used as biomarkers of disease severity or progression of COPD.
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Affiliation(s)
- Marevic Sanja
- a Department of Medical Biochemistry and Hematology , University Hospital for Infectious Diseases ''Dr. Fran Mihaljevic'' , Zagreb , Croatia
| | - Petrik Jozsef
- b Faculty of Pharmacy and Biochemistry, Department of Medical Biochemistry and Hematology , University of Zagreb , Zagreb , Croatia
| | - Popovic Grle Sanja
- c Clinic for Lung Diseases, Jordanovac , University Hospital Centre Zagreb , Zagreb , Croatia
| | - Cepelak Ivana
- c Clinic for Lung Diseases, Jordanovac , University Hospital Centre Zagreb , Zagreb , Croatia
| | - Grgic Ivana
- d Department of Molecular Diagnostics and Flow Cytometry , University Hospital for Infectious Diseases ''Dr. Fran Mihaljevic'' , Zagreb , Croatia
| | - Gorenec Lana
- d Department of Molecular Diagnostics and Flow Cytometry , University Hospital for Infectious Diseases ''Dr. Fran Mihaljevic'' , Zagreb , Croatia
| | | | - Laskaj Renata
- a Department of Medical Biochemistry and Hematology , University Hospital for Infectious Diseases ''Dr. Fran Mihaljevic'' , Zagreb , Croatia
| | - Zidovec Lepej Snjezana
- d Department of Molecular Diagnostics and Flow Cytometry , University Hospital for Infectious Diseases ''Dr. Fran Mihaljevic'' , Zagreb , Croatia
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Kim TH, Oh DK, Oh YM, Lee SW, Do Lee S, Lee JS. Fibrinogen as a potential biomarker for clinical phenotype in patients with chronic obstructive pulmonary disease. J Thorac Dis 2018; 10:5260-5268. [PMID: 30416773 DOI: 10.21037/jtd.2018.08.52] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Under the Food and Drug Administration's drug development tool qualification program, fibrinogen is the first biomarker drug development tool used in chronic obstructive pulmonary disease (COPD). However, the correlation between fibrinogen and exacerbations among Korean patients with COPD remains unclear. Methods In this retrospective cross-sectional study, we included patients with COPD for whom plasma fibrinogen assessment results, without exacerbation, were available. Then, we compared subgroups according to fibrinogen level (threshold: 350 mg/dL). We used multivariate linear regression analysis to investigate the clinical phenotype of COPD with high fibrinogen level, analyzed the correlation between the COPD severity indexes and fibrinogen level. Results Of 140 patients, we confirmed 48 (34.3%) patients in the high-level fibrinogen group. The high-level group demonstrated a medical history of more exacerbations than the low-level group. Lung functions [forced expiratory volume in 1 s (FEV1), forced vital capacity, and 6-minute walk distance] were more deteriorated in the high-level group. Multivariate regression analysis revealed that fibrinogen level was associated with high COPD assessment test score, and experience of exacerbation. Fibrinogen level exhibited a statistically significant positive correlation with COPD severity indexes. Conclusions High fibrinogen level seems to reflect frequent exacerbation and severe symptomatic phenotypes in Korean patients with COPD.
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Affiliation(s)
- Tae Hoon Kim
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Dong Kyu Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeon-Mok Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sei Won Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Do Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Seung Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Is It Time to Change the Definition of Acute Exacerbation of Chronic Obstructive Pulmornary Disease? What Do We Need to Add? Med Sci (Basel) 2018; 6:medsci6020050. [PMID: 29904014 PMCID: PMC6024857 DOI: 10.3390/medsci6020050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 06/10/2018] [Accepted: 06/11/2018] [Indexed: 12/27/2022] Open
Abstract
Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) are associated with increased mortality, rate of hospitalization, use of healthcare resources, and have a negative impact on disease progression, quality of life and lung function of patients with chronic obstructive pulmonary disease (COPD). There is an imperative need to homogenize the definition of AECOPD because the incidence of exacerbations has a significant influence or implication on treatment decision making, particularly in pharmacotherapy and could impact the outcome or change the statistical significance of a therapeutic intervention in clinical trials. In this review, using PubMed searches, we have analyzed the weaknesses and strengths of the different used AECOPD definitions (symptom-based, healthcare-based definition or the combinations of both), as well as the findings of the studies that have assessed the relationship of different biomarkers with the diagnosis, etiology and differential diagnosis of AECOPD and the progress towards the development of a more precise definition of COPD exacerbation. Finally, we have proposed a simple definition of AECOPD, which must be validated in future clinical trials to define its accuracy and usefulness in daily practice.
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Niemeyer BF, Zhao P, Tuder RM, Benam KH. Advanced Microengineered Lung Models for Translational Drug Discovery. SLAS DISCOVERY 2018; 23:777-789. [PMID: 29447055 DOI: 10.1177/2472555218760217] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Lung diseases impose a significant socioeconomic burden and are a leading cause of morbidity and mortality worldwide. Moreover, respiratory medicine, unlike several other therapeutic areas, faces a disappointingly low number of new approved therapies. This is partly due to lack of reliable in vitro or in vivo models that can reproduce organ-level complexity and pathophysiological responses of human lung. Here, we examine new opportunities in application of recently emerged organ-on-chip technology to model human lung alveolus and small airway in preclinical drug development and biomarker discovery. We also discuss challenges that need to be addressed in coming years to further enhance the physiological and clinical relevance of these microsystems, enable their increased accessibility, and support their leap into personalized medicine.
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Affiliation(s)
- Brian F Niemeyer
- 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Peng Zhao
- 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Rubin M Tuder
- 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Kambez H Benam
- 1 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.,2 Department of Bioengineering, University of Colorado Denver, Aurora, CO, USA
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35
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Papaioannou AI, Konstantelou E, Papaporfyriou A, Bartziokas K, Spathis A, Bakakos P, Loukides S, Koulouris N, Papiris S, Kostikas K. Serum Surfactant Protein Levels in Patients Admitted to the Hospital with Acute COPD Exacerbation. Lung 2018; 196:201-205. [DOI: 10.1007/s00408-018-0099-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 02/07/2018] [Indexed: 11/28/2022]
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Celli BR, Locantore N, Tal-Singer R, Riley J, Miller B, Vestbo J, Yates JC, Silverman EK, Owen CA, Divo M, Pinto-Plata V, Wouters EFM, Faner R, Agusti A. Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. Eur Respir J 2018; 51:51/2/1702146. [PMID: 29437944 DOI: 10.1183/13993003.02146-2017] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 11/20/2017] [Indexed: 11/05/2022]
Abstract
We tested whether emphysema progression accompanies enhanced tissue loss in other body compartments in 1817 patients from the ECLIPSE chronic obstructive pulmonary disease (COPD) cohort.Clinical and selected systemic biomarker measurements were compared in subjects grouped by quantitative tomography scan emphysema quartiles using the percentage of low attenuation area (LAA%). Lowest and highest quartile patients had amino-acid metabolomic profiles. We related LAA% to 3 years decline in lung function (forced expiratory volume in 1 s (FEV1)), body mass index (BMI), fat-free mass index (FFMI) and exacerbations, hospitalisations and mortality rates.Participants with more baseline emphysema had lower FEV1, BMI and FFMI, worse functional capacity, and less cardiovascular disease but more osteoporosis. Systemic C-reactive protein and interleukin-6 levels were similar among groups, but club cell protein 16 was higher and interleukin-8, surfactant protein D and soluble receptor for advanced glycation end product were lower with more emphysema. Metabolomics differed between extreme emphysema quartiles. Patients with more emphysema had accelerated FEV1, BMI and FFMI decline and more exacerbations, hospitalisations and mortality.COPD patients with more emphysema undergo excessive loss of pulmonary and extrapulmonary tissue, which is probably related to abnormal tissue maintenance. Because of worse clinical outcomes, we propose this subgroup be named the multi-organ loss of tissue (MOLT) COPD phenotype.
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Affiliation(s)
- Bartolome R Celli
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | - John Riley
- GSK Research and Development, Stevenage, UK
| | - Bruce Miller
- GSK Research and Development, King of Prussia, PA, USA
| | - Jørgen Vestbo
- Dept of Respiratory Medicine, Odense University Hospital, and Clinical Institute, University of Southern Denmark, Odense, Denmark.,Translational Medicine, Manchester Academic Health Sciences Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, UK
| | - Julie C Yates
- GSK Research and Development, Research Triangle Park, NC, USA
| | - Edwin K Silverman
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Caroline A Owen
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Miguel Divo
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Victor Pinto-Plata
- Pulmonary and Critical Care Medicine Division, Baystate Medical Center, Springfield, MA, USA
| | - Emiel F M Wouters
- Dept of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Rosa Faner
- CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Alvar Agusti
- CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Respiratory Institute, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
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Predictors of short-term LAMA ineffectiveness in treatment naïve patients with moderate to severe COPD. Wien Klin Wochenschr 2018; 130:247-258. [PMID: 29322375 DOI: 10.1007/s00508-017-1307-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 12/18/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND No specific (only subgroup) recommendations for the use of long-acting muscarinic antagonists in chronic obstructive pulmonary disease (COPD) exist. The aim of this exploratory hypothesis generating study was to assess whether different phenotypic/endotypic characteristics could be determinants of the short-term ineffectiveness of the initial tiotropium bromide monotherapy in treatment naïve moderate to severe COPD patients. METHODS A total of 51 consecutively recruited COPD patients were followed for 3 months after the initial evaluation and prescribed initial treatment (tiotropium). Short-term treatment ineffectiveness was assessed as a composite measure comprising COPD exacerbations, need for additional treatment, and no improvement in functional parameters, e.g. 6‑min walking test (6MWT), body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index and forced expiratory volume in 1 s (FEV1), and as single components. RESULTS Treatment ineffectiveness was significantly associated with baseline hemoglobin level, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) scale and BODE index (p = 0.002). Incident exacerbation during the follow-up was associated with baseline bronchoalveolar lavage fluid (BALF) alpha-amylase level and CAT score (p < 0.001), and change in treatment with leukocyte count, 6MWT desaturation and fatigue (p < 0.001). No improvement in 6MWT was associated with baseline CAT score, body mass index, mMRC, fatigue, 6MWT and BODE index (p = 0.002). No improvement in BODE index was associated with leukocyte count, serum interleukin 8 (IL-8) and BALF albumin levels (p < 0.001); and no improvement in FEV1 with CAT score, baseline vital capacity and BALF tumor necrosis factor alpha (TNF-alpha) level (p < 0.001). CONCLUSION Our results suggest that there is a possibility to identify predictors of short-term tiotropium ineffectiveness in patients with moderate to severe COPD.
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Abstract
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is estimated to become the third leading cause of death in 2020. The ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study, funded by GlaxoSmithKline, is an observational study designed to define outcomes that can be used as endpoints in clinical trials in individuals with COPD. It allowed us to describe the heterogeneity of COPD, the stability of the exacerbation phenotype, and the factors associated with a progressive decline in lung function and the progression of emphysema on computed tomography scans. The cohort was also used to define genetic factors and biomarkers associated with COPD and disease progression. This review considers how the results from ECLIPSE can inform our understanding of the lung disease associated with alpha-1 antitrypsin deficiency.
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39
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Cloonan SM, Mumby S, Adcock IM, Choi AMK, Chung KF, Quinlan GJ. The "Iron"-y of Iron Overload and Iron Deficiency in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2017; 196:1103-1112. [PMID: 28410559 DOI: 10.1164/rccm.201702-0311pp] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Suzanne M Cloonan
- 1 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York
| | | | | | - Augustine M K Choi
- 1 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.,3 New York-Presbyterian Hospital, New York, New York
| | | | - Gregory J Quinlan
- 4 Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom; and
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Acartürk Tunçay E, Karakurt Z, Aksoy E, Saltürk C, Gungor S, Ciftaslan N, Irmak İ, Yavuz D, Ocakli B, Adıgüzel N. Eosinophilic and non-eosinophilic COPD patients with chronic respiratory failure: neutrophil-to-lymphocyte ratio as an exacerbation marker. Int J Chron Obstruct Pulmon Dis 2017; 12:3361-3370. [PMID: 29200843 PMCID: PMC5703161 DOI: 10.2147/copd.s147261] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Aim Increased dyspnea, sputum volume, and purulence are subjective symptoms in COPD patients. To diagnose COPD exacerbations with chronic respiratory failure (CRF) and to assess the requirement for antibiotic treatment, physicians require more objective criteria. We aimed to investigate whether neutrophil-to-lymphocyte ratio (NLR) can be used as an infectious exacerbation marker in COPD patients with CRF. Patients and methods This retrospective cross-sectional study was performed in the intensive care outpatient clinic of a tertiary training hospital between 2014 and 2015. Patients admitted with CRF due to COPD and who had complete blood count (CBC) results were enrolled. CBC results and C-reactive protein (CRP) levels were obtained from the hospital online database. The “modified exacerbation model (MEM)” was defined as follows: exacerbation A, leukocytes ≥12,000/mm3, CRP >10 mg/dL; exacerbation B, leukocytes ≥10,000/mm3, CRP >10 mg/dL; exacerbation C, leukocytes ≥10,000/mm3, CRP >8 mg/dL; exacerbation D, leukocytes ≥10,000/mm3, CRP >5 mg/dL. The cutoff value of NLR was defined for each model. Patients were split into two groups based on the NLR cutoff value according to the “NLR exacerbation model” and further subgrouped according to peripheral eosinophil percentage (eosinophils ≥2% and <2%) and compared with the MEM. Results A total of 1,066 COPD patients (430 females, 40.3%), with a mean age of 66±13 years, were included. A NLR cutoff value of 3.54 (NLR ≥3.54, n=366, 34%) showed the highest sensitivity and specificity for model A (78%, 69%), model B (63%, 71%), model C (61%, 72%), and model D (58%, 72%). Peripheral eosinophilia (PE ≥2%) was present in 48 patients (4.5%). The ratio of patients with PE <2% in the NLR ≥3.54 group was significantly higher in the MEM (P<0.001). Conclusion The NLR presents an attractive option as an exacerbation marker in COPD patients with CRF due to its simplicity and cost-effectiveness. In COPD patients with CRF, where the NLR is ≥3.54, PE levels are <2%, and subjective symptoms are present, antibiotic treatment should be considered.
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Affiliation(s)
- Eylem Acartürk Tunçay
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Zuhal Karakurt
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Emine Aksoy
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Cuneyt Saltürk
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Sinem Gungor
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nezihe Ciftaslan
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - İlim Irmak
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Dilek Yavuz
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Birsen Ocakli
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Nalan Adıgüzel
- Respiratory Intensive Care Unit, Sureyyapaşa Chest Diseases and Thoracic Surgery Education and Research Hospital, University of Health Sciences, Istanbul, Turkey
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Zhou XM, Hou G, Gu DX, Wang QY, Zhao L. Peroxisome proliferator-activated receptor-γ in induced sputum is correlated with MMP-9/TIMP-1 imbalance and formation of emphysema in COPD patients. J Thorac Dis 2017; 9:3703-3710. [PMID: 29268377 DOI: 10.21037/jtd.2017.09.10] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Background The development of chronic obstructive pulmonary disease (COPD) is modulated by the symmetry of matrix metalloproteinases (MMPs) and the counter-acting tissue inhibitors of metalloproteinases (TIMPs). We investigated the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) expression and the imbalance of MMP-9/TIMP-1 in the induced sputum of stable COPD patients. Methods Sixty-six stable COPD patients were enrolled and the induced sputum samples were gathered. The correlation between PPARγ and other index, including MMP-9, TIMP-1, pulmonary function and the index of emphysema-the percentage of low attenuation area (LAA%), was analyzed. Results PPARγ and TIMP-1 concentrations were decreased and the concentration of MMP-9 and the ratio of MMP9/TIMP1 were enhanced in the induced sputum of COPD patients, compared to the healthy controls. Among COPD patients, those with worse lung function or patients with emphysema exhibited increased MMP-9 expression with decreased TIMP-1 and PPARγ expression. Besides, the concentration of PPARγ of the induced sputum was correlated with the forced expiratory volume in one second percentage (FEV1%) positively and the expression of TIMP-1; while it was negatively correlated with the residual volume (RV), RV/total lung capacity (TLC), LAA%, and MMP-9 expression. Conclusions Our findings reveal the protective role of PPARγ in the maintenance of the dynamic balance of MMP-9/TIMP-1 in COPD, thus providing evidence on which to base the potential COPD treatment.
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Affiliation(s)
- Xiao-Ming Zhou
- Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Shenyang 110004, China.,Institute of Respiratory Disease, China Medical University, Shenyang 110001, China
| | - Gang Hou
- Institute of Respiratory Disease, China Medical University, Shenyang 110001, China.,Department of Respiratory Medicine, the First Hospital, China Medical University, Shenyang 110001, China
| | - Dong-Xue Gu
- Department of Respiratory Medicine, People's Hospital of Liaoning Province, Shenyang 110016, China
| | - Qiu-Yue Wang
- Institute of Respiratory Disease, China Medical University, Shenyang 110001, China.,Department of Respiratory Medicine, the First Hospital, China Medical University, Shenyang 110001, China
| | - Li Zhao
- Department of Respiratory Medicine, Shengjing Hospital, China Medical University, Shenyang 110004, China.,Institute of Respiratory Disease, China Medical University, Shenyang 110001, China
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Izquierdo Alonso JL. Futuro de los marcadores biológicos en la EPOC. Arch Bronconeumol 2017; 53:541-542. [DOI: 10.1016/j.arbres.2017.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 04/14/2017] [Accepted: 04/18/2017] [Indexed: 10/19/2022]
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Koo HK, Kang HK, Song P, Park HK, Lee SS, Jung H. Systemic White Blood Cell Count as a Biomarker Associated with Severity of Chronic Obstructive Lung Disease. Tuberc Respir Dis (Seoul) 2017; 80:304-310. [PMID: 28747965 PMCID: PMC5526959 DOI: 10.4046/trd.2017.80.3.304] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 12/11/2016] [Accepted: 02/23/2017] [Indexed: 12/21/2022] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD), is a chronic inflammatory disorder. We evaluated whether white blood cell (WBC) count, is associated with the severity of COPD, independent of other inflammatory conditions, such as metabolic syndrome. Methods The WBC counts were compared between 1227 COPD patients and 8679 non-COPD adults older than 40. The relationships between the WBC count, lung function, and symptoms score in COPD patients, were determined, using general linear regression analyses. Results The WBC count was negatively associated with forced vital capacity (FVC, L), FVC (% predicted), forced expiry volume in one second (FEV1, L), and FEV1 (% predicted) in COPD patients. Additionally, the WBC count was independently associated with the quality of life measure, by EQ5D-index score. However, this relationship between WBC count, and disease severity, was not significant in current smokers, because of the confounding effect of smoking, on the WBC count. Conclusion The WBC count is associated with current smoking status and COPD severity, and a risk factor for poor lung function, and quality of life, especially in non-currently smoking COPD patients. The WBC count can be used, as an easily measurable COPD biomarker.
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Affiliation(s)
- Hyeon-Kyoung Koo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Hyung Koo Kang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Pamela Song
- Department of Neurology, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Hye Kyeong Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Sung-Soon Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Hoon Jung
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
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Fukuhara A, Saito J, Sato S, Saito K, Fukuhara N, Tanino Y, Wang X, Rinno K, Suzuki H, Munakata M. The association between risk of airflow limitation and serum uric acid measured at medical health check-ups. Int J Chron Obstruct Pulmon Dis 2017; 12:1213-1219. [PMID: 28458533 PMCID: PMC5402911 DOI: 10.2147/copd.s126249] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The prevalence of COPD and asthma is increasing all over the world; however, their morbidities are thought to be greatly underestimated because of unawareness of patients’ conditions and respiratory symptoms. Spirometry is useful for the early detection of COPD and asthma with airflow limitation (AL), although it is not yet widely used for screening in epidemiological and primary care settings. A simple predictive marker used in combination with spirometry for AL is expected to be established. In medical health check-ups, serum uric acid (s-UA) is measured when screening for gout and has recently been suggested to have an association with several respiratory disorders, including asthma and COPD. However, whether s-UA influences the development of AL remains unclear. Therefore, the aims of this study were to examine the relationship between AL and s-UA and to investigate s-UA as a potential auxiliary marker for predicting AL risk in medical health check-ups. A total of 8,662 subjects aged >40 years were included. They were administered a simple questionnaire and assessed using pulmonary function tests, blood pressure (BP) measurements, and blood samplings. One hundred and fifty-six subjects (1.8%) had AL, just 29% of whom had experienced respiratory symptoms. The subjects with AL had significantly higher s-UA levels compared with never-smoking subjects without AL. Forced expiratory volume in 1 second (FEV1) %predicted showed significant correlations with age, smoking index, body mass index (BMI), mean BP, white blood cells, hemoglobin A1c, s-UA, and high-density lipoprotein cholesterol. In multiple logistic regression analysis, s-UA, in addition to age, smoking index, respiratory symptoms, and BMI, was independently associated with AL. In conclusion, elevated s-UA levels, together with respiratory symptoms, high smoking index, and weight loss, may epidemiologically predict the development of AL risk.
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Affiliation(s)
- Atsuro Fukuhara
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Junpei Saito
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Suguru Sato
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Kazue Saito
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Naoko Fukuhara
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Yoshinori Tanino
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Xintao Wang
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
| | - Katsuaki Rinno
- General Examination Center, Fukushima Preservation Service Association of Health, Fukushima, Japan
| | - Hitoshi Suzuki
- General Examination Center, Fukushima Preservation Service Association of Health, Fukushima, Japan
| | - Mitsuru Munakata
- Department of Pulmonary Medicine, School of Medicine, Fukushima Medical University
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45
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Keene JD, Jacobson S, Kechris K, Kinney GL, Foreman MG, Doerschuk CM, Make BJ, Curtis JL, Rennard SI, Barr RG, Bleecker ER, Kanner RE, Kleerup EC, Hansel NN, Woodruff PG, Han MK, Paine R, Martinez FJ, Bowler RP, O’Neal WK. Biomarkers Predictive of Exacerbations in the SPIROMICS and COPDGene Cohorts. Am J Respir Crit Care Med 2017; 195:473-481. [PMID: 27579823 PMCID: PMC5378424 DOI: 10.1164/rccm.201607-1330oc] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 08/30/2016] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Chronic obstructive pulmonary disease exacerbations are associated with disease progression, higher healthcare cost, and increased mortality. Published predictors of future exacerbations include previous exacerbation, airflow obstruction, poor overall health, home oxygen use, and gastroesophageal reflux. OBJECTIVES To determine the value of adding blood biomarkers to clinical variables to predict exacerbations. METHODS Subjects from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) (n = 1,544) and COPDGene (Genetic Epidemiology of COPD) (n = 602) cohorts had 90 plasma or serum candidate proteins measured on study entry using Myriad-RBM multiplex panels. We defined total exacerbations as subject-reported worsening in respiratory health requiring therapy with corticosteroids and/or antibiotics, and severe exacerbations as those leading to hospitalizations or emergency room visits. We assessed retrospective exacerbations during the 12 months before enrollment and then documented prospective exacerbations in each cohort. Exacerbations were modeled for biomarker associations with negative binomial regression including clinical covariates (age, sex, percent predicted FEV1, self-reported gastroesophageal reflux, St. George's Respiratory Questionnaire score, smoking status). We used the Stouffer-Liptak test to combine P values for metaanalysis. MEASUREMENTS AND MAIN RESULTS Between the two cohorts, 3,471 total exacerbations (1,044 severe) were reported. We identified biomarkers within each cohort that were significantly associated with a history of exacerbation and with a future exacerbation, but there was minimal replication between the cohorts. Although established clinical features were predictive of exacerbations, of the blood biomarkers only decorin and α2-macroglobulin increased predictive value for future severe exacerbations. CONCLUSIONS Blood biomarkers were significantly associated with the occurrence of exacerbations but were not robust between cohorts and added little to the predictive value of clinical covariates for exacerbations.
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Affiliation(s)
- Jason D. Keene
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | - Katerina Kechris
- Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Gregory L. Kinney
- Department of Biostatics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | | | - Claire M. Doerschuk
- Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | - Jeffrey L. Curtis
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
- VA Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Stephen I. Rennard
- Division of Pulmonary and Critical Care Medicine, University of Nebraska, Omaha, Nebraska
| | - R. Graham Barr
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - Eugene R. Bleecker
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Richard E. Kanner
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah
| | - Eric C. Kleerup
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Nadia N. Hansel
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Prescott G. Woodruff
- Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, School of Medicine, San Francisco, California; and
| | - MeiLan K. Han
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Robert Paine
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah
| | - Fernando J. Martinez
- Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York
| | | | - Wanda K. O’Neal
- Marsico Lung Institute/Cystic Fibrosis Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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46
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Sng JJ, Prazakova S, Thomas PS, Herbert C. MMP-8, MMP-9 and Neutrophil Elastase in Peripheral Blood and Exhaled Breath Condensate in COPD. COPD 2016; 14:238-244. [PMID: 27880043 DOI: 10.1080/15412555.2016.1249790] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is characterised by progressive and irreversible airflow limitation associated with chronic inflammation involving cytokines and metalloproteinases (MMPs). MMP-8, MMP-9 and neutrophil elastase (NE) are known to be implicated in COPD but the factors influencing activation and suppression remain unclear. This study aimed to compare MMP-8, MMP-9 and NE in the peripheral blood of COPD patients and controls and to likewise assess exhaled breath condensate (EBC) for these MMPs. Peripheral blood micro(mi)RNA139-5p levels, which may regulate MMPs in COPD, were also measured. Blood and EBC were collected from COPD patients (stable and during exacerbations) and healthy controls. Expression of mRNA for MMP-8, MMP-9, NE and miRNA-139-5p expression in peripheral blood mononuclear cells (PBMCs) was measured using qRT-PCR. MMP-8, MMP-9 and NE protein in plasma as well as MMP-8 and MMP-9 protein in EBC were analysed by enzyme-linked immunoassays. PBMCs from COPD patients showed greater expression of mRNA for MMP-8 (p = 0.0004), MMP-9 (p = 0.0023) and NE (p = 0.0019). PBMC expression of mRNA for NE was significantly higher in COPD exacerbations compared to stable cases (p < 0.05). Expression of mRNA for MMP-9 and NE correlated negatively with spirometry in patients (p < 0.05). Plasma from COPD patients showed greater levels of protein for MMP-8 (p = 0.003), MMP-9 (p = 0.046) and NE (p = 0.018). MMP-8 protein levels were lower in the EBC of COPD patients (p < 0.0001). In PBMCs, enhanced expression of mRNA for MMP-9 and NE is associated with COPD and may correlate with disease severity and exacerbations.
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Affiliation(s)
- JieHao Joshua Sng
- a Inflammation and Infection Research, School of Medical Sciences, UNSW Australia , Sydney , NSW , Australia.,b Department of Respiratory Medicine , Prince of Wales Hospital , Randwick , NSW , Australia
| | - Silvie Prazakova
- b Department of Respiratory Medicine , Prince of Wales Hospital , Randwick , NSW , Australia
| | - Paul S Thomas
- a Inflammation and Infection Research, School of Medical Sciences, UNSW Australia , Sydney , NSW , Australia.,b Department of Respiratory Medicine , Prince of Wales Hospital , Randwick , NSW , Australia
| | - Cristan Herbert
- a Inflammation and Infection Research, School of Medical Sciences, UNSW Australia , Sydney , NSW , Australia
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47
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Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip. Cell Syst 2016; 3:456-466.e4. [DOI: 10.1016/j.cels.2016.10.003] [Citation(s) in RCA: 171] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Revised: 08/15/2016] [Accepted: 10/05/2016] [Indexed: 12/21/2022]
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48
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Sand JMB, Leeming DJ, Byrjalsen I, Bihlet AR, Lange P, Tal-Singer R, Miller BE, Karsdal MA, Vestbo J. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD - results from the ECLIPSE study. Respir Res 2016; 17:125. [PMID: 27716343 PMCID: PMC5050854 DOI: 10.1186/s12931-016-0440-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 09/21/2016] [Indexed: 12/31/2022] Open
Abstract
Background There is a need to identify individuals with COPD at risk for disease progression and mortality. Lung tissue remodeling is associated with the release of extracellular matrix (ECM) fragments into the peripheral circulation. We hypothesized that ECM remodeling was associated with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling. Methods Biomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Validated immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used. Multivariate models were used to assess the prognostic value of these biomarkers. Results Thirty subjects (3.0 %) died during follow-up. Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers. All collagen biomarkers were significantly elevated in non-survivors compared to survivors. Mortality risk was significantly increased for subjects with collagen remodeling biomarkers in the upper quartile, especially for the degradation fragment of collagen type IV C6M (hazard ratio 6.6 [95 % confidence interval 2.9-15.2], P < 0.0001) after adjusting for relevant confounders. Conclusions Serological biomarkers of collagen remodeling were strongly associated with mortality in subjects with COPD indicating that assessment of tissue turnover in the parenchyma and small airways may be useful in the prognosis of COPD. Trial registration NCT00292552, GSK Study No. SCO104960. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0440-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jannie M B Sand
- Nordic Bioscience, Herlev, Denmark. .,Section of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.
| | | | | | | | - Peter Lange
- Section of Social Medicine, Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.,Section of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark
| | - Ruth Tal-Singer
- Respiratory Therapy Area Unit, GSK Research and Development, King of Prussia, PA, USA
| | - Bruce E Miller
- Respiratory Therapy Area Unit, GSK Research and Development, King of Prussia, PA, USA
| | | | - Jørgen Vestbo
- Centre for Respiratory Medicine and Allergy, Manchester Academic Science Centre, The University of Manchester and University Hospital South Manchester NHS Foundation Trust, Manchester, UK
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49
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Nicholson GC, Holloway RA, Leaker BR, Kilty I, Salganik M, Tan L, Barnes PJ, Donnelly LE. A novel flow cytometric-based method to measure kinase inhibition in sputum from COPD subjects. BMJ Open Respir Res 2016; 3:e000140. [PMID: 27403320 PMCID: PMC4932304 DOI: 10.1136/bmjresp-2016-000140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 06/03/2016] [Indexed: 12/05/2022] Open
Abstract
Introduction Janus kinases (JAKs) regulate inflammatory gene expression through phosphorylation of signal transducer and activator of transcription (STAT) proteins. Expression of STAT proteins is increased in chronic obstructive pulmonary disease (COPD), and may be involved in driving chronic inflammation. Oral JAK inhibitors are effective as anti-inflammatory therapy but exhibit dose-limiting adverse effects. Development of inhaled compounds would be enhanced by robust biomarkers that directly reflect the anti-inflammatory and pharmacological activity in the lung. Methods A novel flow cytometry assay was developed to measure STAT1 phosphorylation in sputum inflammatory cells. The standard sputum processing method was refined to improve sputum cell viability. The flow cytometric assay was used to assess the reproducibility of the measurement of STAT1 phosphorylation and the in vitro activity of a pan JAK-inhibitor on three separate visits in patients with COPD. Results Upregulation of STAT1 phosphorylation was measured following in vitro IFNγ stimulation of sputum macrophages (stimulated/unstimulated ratio 1.57; p<0.00001). Upregulation was inhibited following in vitro preincubation with a pan JAK-inhibitor (inhibited+stimulated/unstimulated ratio 0.97). STAT1 phosphorylation activity could only be measured in macrophages. Conclusions Sputum from patients with COPD can be used to reproducibly measure phospho-STAT expression in sputum macrophages. The flow cytometry-based method can be used to evaluate kinase inhibitors in vitro and subsequently in ex vivo studies. The assay is particularly useful for the assessment of inhaled compounds where whole blood assays may not be relevant.
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Affiliation(s)
| | - R A Holloway
- Airways Disease Section , National Heart & Lung Institute, Imperial College , London , UK
| | - B R Leaker
- Respiratory Clinical Trials Ltd , London , UK
| | - I Kilty
- Pfizer , Cambridge, Massachusetts , USA
| | | | - L Tan
- Pfizer , Cambridge, Massachusetts , USA
| | - P J Barnes
- Airways Disease Section , National Heart & Lung Institute, Imperial College , London , UK
| | - L E Donnelly
- Airways Disease Section , National Heart & Lung Institute, Imperial College , London , UK
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50
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Kleniewska A, Walusiak-Skorupa J, Piotrowski W, Nowakowska-Świrta E, Wiszniewska M. Comparison of biomarkers in serum and induced sputum of patients with occupational asthma and chronic obstructive pulmonary disease. J Occup Health 2016; 58:333-9. [PMID: 27265531 PMCID: PMC5356940 DOI: 10.1539/joh.15-0317-br] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Objectives: Occupational asthma and chronic obstructive pulmonary disease (COPD) are associated with the airway inflammatory process. The aim of this study was to compare the sputum and serum markers of inflammation in patients with occupational asthma and COPD. Methods: The study group included 20 patients with stable COPD, 24 patients with asthma, and 22 healthy subjects. Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 levels in serum and induced sputum as well as fibrinogen and CRP in serum were determined in all the subjects. Results: Higher concentrations of IL-1β, IL-6, TNF-α, and MMP-9 in induced sputum and an increased concentration of acute-phase proteins in serum were observed in COPD patients compared with healthy subjects. Higher concentrations of IL-1β and MMP-9 in induced sputum and a higher concentration of C-reactive protein (CRP) were detected in COPD patients than in asthmatic subjects. Never smokers with COPD had significantly higher levels of IL-1β and MMP-9 in induced sputum than never smoker controls. There was no significant difference between the serum and sputum levels of cytokines and MMP-9 of never smokers and smokers with COPD. Conclusions: Higher concentrations of IL-1β and MMP-9 in induced sputum and a higher concentration of CRP in serum allow distinguishing between biomarker profiles of COPD patients and asthmatic patients. Occupational exposure induces a systemic proinflammatory state with increased levels of acute-phase proteins in stable COPD patients. MMP-9 and IL-1β concentrations are increased in induced sputum of never smokers with COPD, which is associated with occupational exposure.
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Affiliation(s)
- Aneta Kleniewska
- Department of Occupational Diseases and Environmental Health, Nofer Institute of Occupational Medicine
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