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-α 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 FEV1, FEV1/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 FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/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, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD.

Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients

“…Therefore, it will be of interest to further elucidate the role of RAGE in exacerbations of COPD. Multiple studies have shown that sRAGE is decreased in serum or plasma of COPD patients, which may act to further potentiate the effect of RAGE ligands [9,[14][15][16]. However, in our study, induced sputum and serum levels of sRAGE did not differ between stable disease and exacerbation (sputum levels 159.5±18.7 and 164.0±21.5 pg·mL −1 , respectively) ( fig.…”

“…Furthermore, Ager, the gene encoding RAGE, has been identified by genome-wide association studies as a susceptibility gene for COPD [7,8]. Moreover, the serum levels of soluble RAGE (sRAGE), a decoy receptor for RAGE, were shown to be significantly lower in COPD patients, while the RAGE ligand EN-RAGE (also known as S100 calcium-binding protein (S100)A12) was significantly higher in COPD patients compared with smoking and nonsmoking controls [9]. It is currently unknown, however, whether DAMPs play a role in COPD exacerbations.…”

Generation and Activity of a Humanized Monoclonal Antibody That Selectively Neutralizes the Epidermal Growth Factor Receptor Ligands Transforming Growth Factor-αand Epiregulin

“…Accumulating evidence implicates TGFa as a promising target for several diseases, including Ménétrier's disease (Dempsey et al, 1992), psoriasis (Vassar and Fuchs, 1991), COPD (Cockayne et al, 2012) and CKD (Lautrette et al, 2005;Laouari et al, 2011). For instance, TGFa expression appears mislocalized and overexpressed in the gastric mucosa of patients with Ménétrier's disease (Dempsey et al, 1992) and transgenic mice that overexpress Tgfa in the gastric mucosa show a number of features in common with Ménétrier's disease (Goldenring et al, 1996).…”

“…All of the current drugs that target the EGFR for cancer are associated with a pustulant purulent skin rash predominantly on the face, neck, shoulder, and back, occurring in up to 85% of patients (Li and Perez-Soler, 2009). The EGFR pathway has also been implicated but less well-studied in other diseases, such as atherosclerosis (Nakata et al, 1996;Reape et al, 1997), hypertension (Kagiyama et al, 2002;Flamant et al, 2003), left ventricular hypertrophy (Asakura et al, 2002), arterial remodeling (Taylor et al, 1999), psoriasis (Sergi et al, 2000;Overbeck and Griesinger, 2012), arthritis (Hallbeck et al, 2005;Swanson et al, 2012), chronic obstructive pulmonary disease (COPD) (Cockayne et al, 2012), asthma (Zhen et al, 2007), and chronic kidney disease (CKD) (Terzi et al, 2000;Lautrette et al, 2005;Liu et al, 2012).…”

“…Tgfa protein levels are elevated in human psoriatic skin (Sergi et al, 2000), and targeted overexpression of Tgfa in mouse skin results in thickened epidermis, hair loss and a leukocytic infiltration and granular layer loss characteristic of human psoriasis (Vassar and Fuchs, 1991). Serum Tgfa levels are also elevated in patients with COPD and are significantly associated with disease severity (Cockayne et al, 2012), whereas the conditional overexpression of Tgfa in the adult mouse lung results in progressive pulmonary fibrosis (Hardie et al, 2004). More recently, in an animal model of chronic kidney disease, renal Tgfa protein levels were shown to be markedly increased preceding the development of renal lesions (Laouari et al, 2011), and progressive renal disease was markedly attenuated in mice genetically deficient for Tgfa (Laouari et al, 2012).…”