Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Stolz, Daiana; Leeming, Diana Julie; Kristensen, Jakob; Karsdal, Morten A.; Boersma, Wim; Louis, Renaud; Milenković, Branislava; Κostikas, Κonstantinos; Blasi, Francesco; Aerts, Joachim; Sand, J.M.B.; Wouters, Emiel F.M.; Rohde, Gernot; Prat, Cristina; Torres, Antoni; Welte, Tobias; Roth, Michael; Papakonstantinou, Eleni; Tamm, Michael

doi:10.1016/j.chest.2016.08.1440

Cited by 62 publications

(54 citation statements)

References 27 publications

(38 reference statements)

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“…This is in line with what is known for hepatitis and diabetes, where the SNP rs8099917 GG genotype is considered to be the risk genotype and the SNP rs12979860 CC genotype the protective genotype [35][36][37]. The IFNL3 polymorphisms predict response to treatment in patients with hepatitis C [27,30,31]. We found that the prevalence of malignancy was increased among patients with the rs8099917 GG genotype.…”

Section: Discussionsupporting

confidence: 86%

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IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

et al. 2018

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BackgroundInterferon lambdas (IFNLs) have important anti-viral/bacterial and immunomodulatory functions in the respiratory tract. How do IFNLs impact COPD and its exacerbations?MethodsFive hundred twenty eight patients were recruited in a prospective observational multicentre cohort (PROMISE) study. The genetic polymorphisms (rs8099917 and rs12979860) within the IFNL3/4 gene region and circulating levels of IFNL3 in COPD patients were determined and associated with disease activity and outcome during a median follow-up of 24 months.ResultsThe GG genotype significantly influenced severe exacerbation rate (42 vs. 23%; p = 0.032) and time to severe exacerbation (HR = 2.260; p = 0.012). Compared to the TT or TG genotypes, the GG genotype was associated with severe dyspnoea (modified medical research council score ≥ median 3; 22 vs 42%, p = 0.030). The CC genotype of the rs12979860 SNP was associated with a poorer prognosis (body mass index, airflow obstruction, dyspnea and exercise capacity index ≥ median 4; 46 vs. 36% TC vs. 20.5% TT; p = 0.031). Patients with stable COPD and at exacerbation had significantly lower circulating IFNL3 compared to healthy controls (p < 0.001 and p < 0.001, respectively). Circulating IFNL3 correlated to post-bronchodilator FEV1%predicted and the tissue maturation biomarker Pro-collagen 3.ConclusionIFNL3/4 polymorphisms and circulating IFNL3 may be associated with disease activity and outcomes in COPD.Trial registrationClinical Trial registration http://www.isrctn.com/ identifier ISRCTN99586989 on 16 April 2008.

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Section: Discussionsupporting

confidence: 86%

“…As previously described [31], serum levels of fragments of collagen type III (C3M), fragments of collagen type VI (C6M), pro-form of collagen type III (Pro-C3) and proform of collagen type VI (Pro-C6) were measured with Nordic Bioscience assays according to the manufacturer's instructions.…”

Section: Collagen Markersmentioning

confidence: 99%

IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

et al. 2018

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“…However, recent published report with the same biomarkers in other well-known COPD cohorts support the findings that C6M and EL-NE are significantly associated with lung function in COPD [73, 74], and have been found to be elevated during exacerbations in a smaller study [56]. …”

Section: Discussionsupporting

confidence: 60%

“…These biological processes deep within the matrix of the lung, may be associated with COPD phenotypes, disease progression, and events such as exacerbations. In direct alignment, the balance between type VI collagen formation and degradation, was shown to be significantly changed as measured by the same protein biomarkers in serum, in COPD patients with exacerbations [56, 73, 74]. Furthermore, type VI collagen remodeling as measured by these biomarkers has been associated with disease progression, defined by change in FEV 1 , and mortality in COPD patients from the ECLIPSE cohort [65].…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

et al. 2017

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BackgroundChronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction and loss of lung tissue mainly consisting of extracellular matrix (ECM). Three of the main ECM components are type I collagen, the main constituent in the interstitial matrix, type VI collagen, and elastin, the signature protein of the lungs. During pathological remodeling driven by inflammatory cells and proteases, fragments of these proteins are released into the bloodstream, where they may serve as biomarkers for disease phenotypes. The aim of this study was to investigate the lung ECM remodeling in healthy controls and COPD patients in the COPDGene study.MethodsThe COPDGene study recruited 10,300 COPD patients in 21 centers. A subset of 89 patients from one site (National Jewish Health), including 52 COPD patients, 12 never-smoker controls and 25 smokers without COPD controls, were studied for serum ECM biomarkers reflecting inflammation-driven type I and VI collagen breakdown (C1M and C6M, respectively), type VI collagen formation (Pro-C6), as well as elastin breakdown mediated by neutrophil elastase (EL-NE). Correlation of biomarkers with lung function, the SF-36 quality of life questionnaire, and other clinical characteristics was also performed.ResultsThe circulating concentrations of biomarkers C6M, Pro-C6, and EL-NE were significantly elevated in COPD patients compared to never-smoking control patients (all p < 0.05). EL-NE was significantly elevated in emphysema patients compared to smoking controls (p < 0.05) and never-smoking controls (p < 0.005), by more than 250%. C1M was inversely associated with forced expiratory volume in 1 s (FEV1) (r = −0.344, p = 0.001), as was EL-NE (r = −0.302, p = 0.004) and Pro-C6 (r = −0.259, p = 0.015). In the patients with COPD, Pro-C6 was correlated with percent predicted Forced Vital Capacity (FVC) (r = 0.281, p = 0.046) and quality of life using SF-36. C6M and Pro-C6, were positively correlated with blood eosinophil numbers in COPD patients (r = 0.382, p = 0.006 and r = 0.351, p = 0.012, respectively).ConclusionsThese data suggest that type VI collagen turnover and elastin degradation by neutrophil elastase are associated with COPD-induced inflammation (eosinophil-bronchitis) and emphysema. Serological assessment of type VI collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials.

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“…Neutrophil elastase-generated fragments of elastin (EL-NE) is different between stable and exacerbation of COPD patients. The serum level of EL-NE is associated with lung function [102]. Elastin breakdown mediated by neutrophil elastase is associated with COPD-induced inflammation [103].…”

Section: Neutrophils In Copdmentioning

confidence: 99%

Advanced Role of Neutrophils in Common Respiratory Diseases

Liu

Pang

Wang

et al. 2017

Journal of Immunology Research

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Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases.

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Systemic Biomarkers of Collagen and Elastin Turnover Are Associated With Clinically Relevant Outcomes in COPD

Abstract: No.: ISRCTN99586989; URL: www.controlled-trials.com.

Cited by 62 publications

References 27 publications

IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

IFNΛ3/4 locus polymorphisms and IFNΛ3 circulating levels are associated with COPD severity and outcomes

Biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in COPD

Advanced Role of Neutrophils in Common Respiratory Diseases

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