Abstract
BackgroundInflammation, both local and systemic, is a hallmark of chronic obstructive pulmonary disease (COPD). Inflammatory mediators such as TNFα and GM-CSF are secreted by lung epithelium, alveolar macrophages and other inflammatory cells and are thought to be important contributors in the pathogenesis of COPD. Indeed, neutrophils are activated by these cytokines and these cells are one of the major inflammatory cell types recruited to the pulmonary compartment of COPD patients. Furthermore, these inflammatory mediators are found in the peripheral blood of COPD patients and, therefore, we hypothesized that TNFα/GM-CSF-induced protein profiles can be found in peripheral neutrophils of COPD patients.MethodsUsing fluorescence 2-dimensional difference gel electrophoresis we investigated differentially regulated proteins in peripheral neutrophils from COPD patients and healthy age-matched control subjects. Furthermore, protein profiles from COPD patients were compared with those of neutrophils of healthy age-matched controls that were stimulated with TNFα and/or GM-CSF in vitro. Protein gels were compared using DeCyder 7.0 software.ResultsWe identified 7 significantly regulated protein spots between peripheral neutrophils from COPD patients and age-matched healthy control subjects. Stimulation of peripheral neutrophils with TNFα, GM-CSF or TNFα + GM-CSF in vitro resulted in 13, 20 and 22 regulated protein spots, respectively. However, these cytokine-induced protein differences did not correspond with the protein differences found in neutrophils from COPD patients.ConclusionThese results show that neutrophils from COPD patients have a unique protein profile compared to neutrophils from healthy age-matched controls. Furthermore, the neutrophil profiles of COPD patients do not reflect putative dominant signals induced by TNFα, GM-CSF or their combination. Our results indicate that systemic neutrophil responses in COPD patients are caused by a unique but subtle interplay between multiple inflammatory signals.
Highlights
Inflammation, both local and systemic, is a hallmark of chronic obstructive pulmonary disease (COPD)
COPD is classified by the guidelines of the Global Initiative for Chronic Obstructive Lung Disease, which is based on lung function parameters: forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) [1]
The individual spotmaps were matched in the biological variation analysis (BVA) software and statistical analysis between healthy controls and COPD patients showed 7 protein spots that were at least 1.10-fold differentially regulated with a p < 0.01 (Figure 1 and Table 2)
Summary
Inflammation, both local and systemic, is a hallmark of chronic obstructive pulmonary disease (COPD) Inflammatory mediators such as TNFa and GM-CSF are secreted by lung epithelium, alveolar macrophages and other inflammatory cells and are thought to be important contributors in the pathogenesis of COPD. It has become increasingly clear that the GOLD classification does not represent the complex local and systemic inflammation in COPD [2,3,4] Part of this inflammatory process is the secretion of inflammatory mediators by lung epithelium, alveolar macrophages and other inflammatory cells [5]. This GM-CSF-induced inhibition was dose-dependent and was confirmed at the protein level by Western blot analysis [22] These results show that integration of multiple cytokine signals can result in a distinct phenotype of the neutrophils
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