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Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.

ABSTRACT: The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-? and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-?) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r ?=? -0.52, p ?=? 0.005 and r ?=? -0.61, p =? 0.023, respectively) compared to patients with coexisting metabolic syndrome (r ?=? -0.25, p ?= ?0.47 and r ?=? -0.15, p ?= ?0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.

SUBMITTER: Cockayne DA

PROVIDER: S-EPMC3373533 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.

Cockayne Debra A DA Cheng Donavan T DT Waschki Benjamin B Sridhar Sriram S Ravindran Palanikumar P Hilton Holly H Kourteva Galina G Bitter Hans H Pillai Sreekumar G SG Visvanathan Sudha S Müller Kai-Christian KC Holz Olaf O Magnussen Helgo H Watz Henrik H Fine Jay S JS

PloS one 20120612 6

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seve ...[more]

PMID: 22701684

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Project description:BackgroundWe hypothesized that particulate matter (PM) gamma activity (gamma radiation associated with PM) is associated with systemic effects.ObjectiveExamine short-term relationships between ambient and indoor exposures to PM gamma activities with systemic inflammation and endothelial activation in chronic obstructive pulmonary disease (COPD) patients.MethodsIn 85 COPD patients from Eastern Massachusetts, USA from 2012 to 2014, plasma C-reactive protein (CRP), interleukin-6 (IL-6), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured seasonally up to four times. We used US EPA RadNet data measuring ambient gamma radiation attached to PM adjusted for background radiation, and estimated in-home gamma radiation exposures using the ratio of in-home-to-ambient sulfur in PM2.5. Linear mixed-effects regression models were used to determine associations between moving averages of PM gamma activities through the week before phlebotomy with these biomarkers. We explored ambient and indoor PM2.5, black carbon (BC), and NO2 as confounders.ResultsAmbient and indoor PM gamma activities measured as energy spectra classes 3 through 9 were positively associated with CRP and IL-6. For example, averaged from phlebotomy day through previous 6 days, each IQR increase in indoor PM gamma activity for each spectra class, was associated with an CRP increase ranging from 7.45% (95%CI: 2.77, 12.4) to 13.4% (95%CI: 5.82, 21.4) and for ambient exposures were associated with an increase of 8.75% (95%CI: -0.57, 18.95) to 14.8% (95%CI: 4.5, 26.0). Indoor exposures were associated with IL-6 increase of 3.56% (95%CI: 0.31, 6.91) to 6.46% (95%CI:1.33, 11.85) and ambient exposures were associated with an increase of 0.03% (95%CI: -6.37, 6.87) to 3.50% (95%CI: -3.15, 10.61). There were no positive associations with sVCAM-1. Sensitivity analyses using two-pollutant models showed similar effects.ConclusionsOur results demonstrate that short-term exposures to environmental PM gamma radiation activities were associated with systemic inflammation in COPD patients.

Project description:BACKGROUND: The inflammatory process in chronic obstructive pulmonary disease (COPD) is characterised by the presence of neutrophils in the lung that are able to synthesise de novo several inflammatory mediators. The local chronic persistent inflammatory response is accompanied by systemic effects such as cytokine induced priming of peripheral leucocytes and muscle wasting. The preactivation or priming of peripheral blood neutrophils was used to gain more insight into the mechanisms of this systemic inflammatory response. METHODS: Gene arrays were performed on peripheral blood neutrophils obtained from healthy donors after stimulation in vitro with tumour necrosis factor (TNF)-alpha, granulocyte-macrophage colony stimulating factor (GM-CSF), or both. The expression of many inflammatory genes was regulated in these cells following stimulation. The expression of inflammatory genes in peripheral blood neutrophils in healthy subjects and those with COPD was measured by real time RT-PCR after stimulation with TNFalpha, GM-CSF, interleukin (IL)-8, fMLP, TNFalpha + GM-CSF, and lipopolysaccharide (LPS). RESULTS: The genes regulated in the gene array with TNFalpha/GM-CSF stimulated neutrophils included cytokines (such as IL-1beta), chemokines (such as IL-8), and adhesion molecules (such as ICAM-1). Disease severity as measured by forced expiratory volume in 1 second (FEV(1)) in COPD patients correlated with expression of several of these genes including IL-1beta (r = -0.540; p = 0.008), MIP-1beta (r = -0.583; p = 0.003), CD83 (r = -0.514; p = 0.012), IL-1 receptor 2 (r = -0.546; p = 0.007), and IL-1 receptor antagonist (r = -0.612; p = 0.002). CONCLUSIONS: These data are consistent with the hypothesis that progression of COPD is associated with the activation of neutrophils in the systemic compartment. De novo expression of inflammatory mediators by peripheral blood neutrophils suggests a pro-inflammatory role for these cells in the pathogenesis of COPD.

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Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.

Publications

Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity.

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