Sputum biomarker profiles in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) and association between pulmonary function
Introduction
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are chronic airway diseases [1], [2] with different causes that share some features in pathologic changes and clinical presentation. In these diseases, there are chronic mucosal and airway inflammation, each with distinct pathophysiologic features, but a common increase in the infiltration of neutrophils [3] in addition to a variety of inflammatory mediators [4]. The pathologic processes in these diseases seem to involve progressive inflammatory responses with elements of tissue remodeling [5], airway obstruction and reduction in expiratory flow rates [6].
In COPD, an abnormal inflammatory response of the lung to noxious particles or gases is present [7]. Although cigarette smoking is the main pathological driver of COPD [8], [9], other factors may be involved. Genetic predisposition could explain why only a proportion of cigarette smokers develop COPD [10]. Other factors include particulates in environmental pollution and exposure to biomass combustion, which may explain why some patients who develop COPD are never-smokers [11].
In CF, the inflammatory response is driven mainly by bacterial infections, especially Pseudomonas species, which leads to tissue breakdown and severe lung damage [12]. Markers of inflammatory activity play an important role for assessment and management of those respiratory diseases [13]. Due to technical reasons, previous investigations of sputum in chronic lung diseases, like CF and COPD, focused on cytology and determination of single inflammatory mediators [14], [15], [16].
The determination of cytokines and chemokines in induced sputum by cytometric bead array (CBA) promises to be of substantial benefit for sputum investigations because numerous analytes can be measured simultaneously with a small sample volume [17]. In addition to this, CBA is faster and more cost effective than ELISA technology.
In our study, CBA was used to determine sputum levels of pro-inflammatory cytokines and chemokines (IL-1β, IL-2, IL-6, IL-8, IL-13, IP-10, INF-γ, MCP-1 and TNF-α) in induced sputum of patients with CF and COPD in comparison to healthy control subjects. We hypothesized, that the analysis of these different pleiotropic inflammatory mediators may lead to pathognomonic patterns for the underlying disease. Furthermore, it was postulated that these patterns of biomarkers show a significant correlation to the clinical status (lung function) of our patients.
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Subjects and selection
Patients were recruited from the Division of Pediatric Pulmonology, Allergy and Cystic fibrosis, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany and the Department of Internal Medicine, Johannes Gutenberg-University Hospital, Mainz, Germany. The population of this study consisted of 19 clinically stable patients with cystic fibrosis (18 were Pseudomonas aeruginosa-infected), 26 clinically stable patients with COPD and 21 non-smoking healthy control subjects. Clinical stability
Results
All nine biomarkers were detectable in nearly every sputum sample derived from patients with CF and COPD and compared to healthy control subjects. However, looking at IP-10, MCP-1, IL-2, IFN-γ and IL-13 some sputum samples were under the limit of detection. Measured parameters were grouped in neutrophilic inflammatory cytokines (Fig. 1A: IL-1β, IL-6 and TNF-α), chemokines (Fig. 1B: IL-8, IP-10 and MCP-1) and TH1/TH2 -cytokines (Fig. 1C: IL-2, IFN-γ and IL-13).
The inflammatory
Discussion
Markers of inflammatory activity are important for the assessment and management of chronic respiratory diseases like CF and COPD [21]. In order to study the local inflammatory response non-invasively, we employed a standardized and validated sputum-induction protocol [18]. Numerous studies have analyzed inflammatory cytokines in sputum, in relation to clinical status [22], [23], [24], [25]. The new CBA technique allows characterization of specific airway biomarker profiles from small sputum
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