transforming-growth-factor-alpha and Pulmonary-Disease--Chronic-Obstructive

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 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-α) 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.

Topics: Acute-Phase Proteins; Aged; Biomarkers; Cohort Studies; Comorbidity; Female; Fibrinogen; Forced Expiratory Volume; Granulocyte Colony-Stimulating Factor; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-3; Lipocalin-2; Lipocalins; Male; Metabolic Syndrome; Multivariate Analysis; Proto-Oncogene Proteins; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Recombinant Fusion Proteins; Regression Analysis; S100 Proteins; S100A12 Protein; Smoking; Transforming Growth Factor alpha

We previously reported that sputum levels of procollagen type I C-terminal peptide (PICP), a marker of ongoing collagen type I deposition, are increased in proportion to airway inflammation in asthma patients.. In this study, we examined the effect of inhaled corticosteroids on increased collagen synthesis in step 2-4 asthmatics.. We compared the sputum PICP concentrations of 25 steroid-naive asthmatics, 25 normal volunteers, and 10 subjects with chronic obstructive pulmonary disease. Asthma subjects were also instructed to start fluticasone propionate treatment, and the percentage of forced expiratory volume in 1 s, sputum eosinophil counts, sputum PICP concentrations, and sputum transforming growth factor-beta-positive cell counts before treatment were compared with those 1 month after treatment.. Sputum PICP concentrations were detected in the following order: asthma group >or= chronic obstructive pulmonary disease group > control group. Asthma patients showing high sputum PICP belonged to step 4, although there was no correlation between sputum PICP and asthma severity. Treatment with fluticasone propionate not only significantly improved the mean percentage of forced expiratory volume in 1 s (from 66.7 to 87.2%), but also decreased the mean sputum eosinophil counts (from 13.4 to 5.8%), the mean sputum PICP concentrations (from 30.8 to 10.2 ng/ml), and the mean sputum tumor growth factor-beta-positive cells (from 11.3 to 2.8%). Nevertheless, a significant difference in sputum PICP concentrations was still observed between the control group and the steroid-treated asthma group.. The present results suggest that inhaled corticosteroid treatment might reduce sputum indexes of collagen metabolism and eosinophilic inflammation in asthma patients.

Topics: Administration, Inhalation; Adult; Aged; Asthma; Biomarkers; Enzyme-Linked Immunosorbent Assay; Eosinophils; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Immunohistochemistry; Leukocyte Count; Male; Middle Aged; Peptide Fragments; Procollagen; Prognosis; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Sputum; Transforming Growth Factor alpha

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the U.S. Because cigarette smoking is so importantly implicated in the pathogenesis of COPD and because mucus hypersecretion plays such an important role in COPD, understanding of the mechanisms of smoking-induced mucus hypersecretion could lead to new therapies for COPD. Cigarette smoke causes mucin overproduction via EGF receptor (EGFR) in airway epithelial cells, but the cellular mechanism remains unknown. Airway epithelial cells contain EGFR proligands on their surfaces, which can be cleaved by metalloprotease and subsequently bind to EGFR resulting in mucin production. We hypothesize that TNF-alpha-converting enzyme (TACE) is activated by cigarette smoke, resulting in increased shedding of EGFR proligand, leading to EGFR phosphorylation and mucin induction in human airway epithelial (NCI-H292) cells. Here we show that cigarette smoke increases MUC5AC production in NCI-H292 cells, an effect that is prevented by an EGFR-neutralizing antibody and by specific knockdown of transforming growth factor-alpha (TGF-alpha) using small interfering RNA (siRNA) for TGF-alpha, implicating TGF-alpha-dependent EGFR activation in the responses. Cigarette smoke increases TGF-alpha shedding, EGFR phosphorylation, and mucin production, which are prevented by metalloprotease inhibitors (GM-6001 and TNF-alpha protease inhibitor-1) and by specific knockdown of TACE with TACE siRNA, implicating TACE in smoking-induced responses. Furthermore, pretreatment with antioxidants prevents smoking-induced TGF-alpha shedding and mucin production, suggesting that reactive oxygen species is involved in TACE activation. These results implicate TACE in smoking-induced mucin overproduction via the TACE-proligand-EGFR signal pathway in NCI-H292 cells.

Topics: ADAM Proteins; ADAM17 Protein; Carcinoma, Mucoepidermoid; Cell Line, Tumor; ErbB Receptors; Gene Expression; Humans; Ligands; Lung Neoplasms; Metalloendopeptidases; Mucin 5AC; Mucins; Phosphorylation; Protein Precursors; Pulmonary Disease, Chronic Obstructive; Reactive Oxygen Species; Respiratory Mucosa; Smoking; Transforming Growth Factor alpha; Tumor Necrosis Factor-alpha; Up-Regulation