Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease
Highlights
► Our goal was to compare local and systemic inflammation in COPD with healthy subjects. ► Besides cell counts, we measured cytokine production by using a cell culture model. ► A neutrophilic inflammation and raised IFN-γ release at both level was found in COPD. ► Systemic TNF-α overproduction correlated with disease severity and inversely with BMI.
Introduction
Chronic obstructive pulmonary disease (COPD) causes a significant health burden worldwide, in terms of morbidity and mortality. COPD is characterized by progressive and not fully reversible airflow limitation. It is a chronic airway inflammatory disease with a systemic component related to repeated inhalation of noxious gas and particles, in particular tobacco smoke [28].
The principal abnormalities in airways are the presence of a persistent inflammatory response as well as a structural remodelling that thickens the airway wall. A destruction of alveoli is also present and leads to the occurrence of emphysema [7]. The epithelial cells are damaged by the inhalation of noxious particles and there is an activation of innate (mainly neutrophils and macrophages) and adaptative immune cells (mainly CD8 cells). These cells are responsible for the release of proteases, cytokines/chemokines and mediators, which lead to inflammation and remodelling. COPD has been seen as a Th1 disease but some data suggest that Th2 cytokine may also play a role [1], [2]. On the other hand some data have suggested that COPD may be favoured by a lack of anti-inflammatory cytokine such as IL-10 [38].
COPD is not only associated with an abnormal inflammatory response in the lung but also with systemic inflammation, including systemic oxidative stress, activation of circulating inflammatory cells and increased levels of circulating inflammatory cytokines [16].
Induced sputum is a recognized non-invasive technique to assess the cellular composition in chronic airway disease including COPD [29]. In addition, induced sputum cell culture has been shown to be a valid model to investigate cytokine production from airway cells in asthma [3], [22], [27], [32].
The purpose of our study was twofold. First, to compare airway and systemic inflammation between COPD and healthy subject and secondly, to assess how this inflammation relates to disease severity in COPD. Here, we evaluated the sputum and blood cell composition as well as the sputum and blood cell cytokine production in 95 COPD and 33 healthy subjects. As for cytokine, we decided to analyse the level of interleukin-4 (IL-4) and interferon-γ (IFN-γ) as markers of the Th2/Th1 balance, TNF-α and IL-10 as pro- and anti-inflammatory cytokines, respectively, and IL-6 as a cytokine playing a role in the transition from innate toward adaptive immunity [18].
Section snippets
Study design and subject characteristics
The demographic and functional characteristics of patients are given in Table 1. COPD patients (n = 95) were recruited from our outpatient clinic and rehabilitation centre CHU-Sart Tilman. Diagnosis of COPD was made according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (post-bronchilator-400 μg salbutamol-ratio FEV1/FVC < 70%). We divided COPD patients in three groups according to GOLD classification of severity (GOLD II: FEV1 < 80% and ⩾50%; GOLD III: FEV1 < 50% and ⩾30%
Theory
COPD prevalence and morbidity continue to increase throughout the world and it represents a significant burden on the healthcare system. It is the fourth leading cause of death in most industrialized countries and it is projected to be the third worldwide by 2020.
Therefore, the identification of biomarkers involved in the immunopathogenesis of COPD is crucial and may provide myriad opportunities for possible intervention. Indeed, such biomarkers may be useful for monitoring disease progression
Patient characteristics
Patients in both groups consisted mostly of men and COPD patients were all current or ex-smokers. Other demographic and treatment characteristics are given in Table 1. The pulmonary function parameters of COPD patients were significantly reduced compared to the healthy volunteers.
Sputum and blood cell counts
Detailed cell counts are given in Table 2. As for sputum COPD were characterized by a raised total sputum cell number (p < 0.01). The proportion of neutrophils (p < 0.0001) and, to a lesser extent, that of eosinophils (p <
Discussion
COPD exhibited a raised airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-α release deficiency that contrasted with a raised IFN-γ production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-γ, IL-10 and TNF-α. Furthermore, we found a significant correlation between the sputum neutrophil count and the disease severity reflected by the GOLD stages. At the systemic level, production of TNF-α also correlated to GOLD
Conclusions
Our study confirms the neutrophilic inflammation in COPD both at the local and the systemic level. It shows raised local and systemic IFN-γ production highlighting the pertinence of Th1 concept in COPD. A systemic enhanced release of TNF-α is also an important feature of COPD which is related to disease severity and BMI.
Acknowledgements
The authors would like to thank all participants of the study and thank the lung function department of the CHU of Liege for their help in the collection of the data. The study was financially supported by the National Fund for Scientific Research (FNRS, Belgium) and TELEVIE (Grant 7.4.642.09.F).
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