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      Proteomic profiling of peripheral blood neutrophils identifies two inflammatory phenotypes in stable COPD patients

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          Abstract

          Background

          COPD is a heterogeneous chronic inflammatory disease of the airways and it is well accepted that the GOLD classification does not fully represent the complex clinical manifestations of COPD and this classification therefore is not well suited for phenotyping of individual patients with COPD. Besides the chronic inflammation in the lung compartment, there is also a systemic inflammation present in COPD patients. This systemic inflammation is associated with elevated levels of cytokines in the peripheral blood, but the precise composition is unknown. Therefore, differences in phenotype of peripheral blood neutrophils in vivo could be used as a read out for the overall systemic inflammation in COPD.

          Method

          Our aim was to utilize an unsupervised method to assess the proteomic profile of peripheral neutrophils of stable COPD patients and healthy age matched controls to find potential differences in these profiles as read-out of inflammatory phenotypes. We performed fluorescence two-dimensional difference gel electrophoresis with the lysates of peripheral neutrophils of controls and stable COPD patients.

          Results

          We identified two groups of COPD patients based on the differentially regulated proteins and hierarchical clustering whereas there was no difference in lung function between these two COPD groups. The neutrophils from one of the COPD groups were less responsive to bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF).

          Conclusion

          This illustrates that systemic inflammatory signals do not necessarily correlate with the GOLD classification and that inflammatory phenotyping can significantly add in an improved diagnosis of single COPD patients.

          Trial registration

          Clinicaltrials.gov: NCT00807469 registered December 11th 2008

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          Most cited references 28

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          Chronic obstructive pulmonary disease

          Summary Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease.
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            Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

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              Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays

              Background Growing knowledge about cellular interactions in the immune system, including the central role of cytokine networks, has lead to new treatments using monoclonal antibodies that block specific components of the immune system. Systemic cytokine concentrations can serve as surrogate outcome parameters of these interventions to study inflammatory pathways operative in patients in vivo. This is now possible due to novel technologies such as multiplex immunoassays (MIA) that allows detection of multiple cytokines in a single sample. However, apparently trivial underappreciated processes, (sample handling and storage, interference of endogenous plasma proteins) can greatly impact the reliability and reproducibility of cytokine detection. Therefore we set out to investigate several processes that might impact cytokine profiles such as blood collecting tubes, duration of storage, and number of freeze thawing cycles. Results Since under physiological conditions cytokine concentrations normally are low or undetectable we spiked cytokines in the various plasma and serum samples. Overall recoveries ranged between 80-120%. Long time storage showed cytokines are stable for a period up to 2 years of storage at -80°C. After 4 years several cytokines (IL-1α, IL-1β, IL-10, IL-15 and CXCL8) degraded up to 75% or less of baseline values. Furthermore we show that only 2 out of 15 cytokines remained stable after several freeze-thawing cycles. We also demonstrate implementation of an internal control for multiplex cytokine immunoassays. Conclusion All together we show parameters which are essential for measurement of cytokines in the context of clinical trials.
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                Author and article information

                Contributors
                Adeletlo@gmail.com
                susanhoonhorst@gmail.com
                C.vanAalst@umcutrecht.nl
                Jeroen.Langereis@radboudumc.nl
                Vera@goldewijk.net
                S.L.Eising@umcutrecht.nl
                n.h.t.ten.hacken@umcg.nl
                j.w.j.lammers@umcutrecht.nl
                +31 88 7557255 , l.koenderman@umcutrecht.nl , L.Koenderman@umcutrecht.nl
                Journal
                Respir Res
                Respir. Res
                Respiratory Research
                BioMed Central (London )
                1465-9921
                1465-993X
                22 May 2017
                22 May 2017
                2017
                : 18
                Affiliations
                [1 ]ISNI 0000000090126352, GRID grid.7692.a, Departments of Respiratory Medicine, , University Medical Center Utrecht, ; Utrecht, The Netherlands
                [2 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Departments of Respiratory Medicine, , University Medical Center Groningen, ; Groningen, The Netherlands
                [3 ]ISNI 0000000090126352, GRID grid.7692.a, Department Respiratory Medicine and Laboratory of Translational Immunology, , University Medical Center Utrecht, ; Heidelberglaan 100, 3583CX Utrecht, The Netherlands
                Article
                586
                10.1186/s12931-017-0586-x
                5440930
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004522, Top Institute Pharma;
                Award ID: TI-108
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

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