Abstract
BackgroundChronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH). Mucin production is activated in part by stimulation of the epidermal growth factor (EGF) receptor pathway through neutrophils and macrophages. How circulating cytokine levels relate to GCH is not clear.MethodsWe performed phlebotomy and bronchoscopy on 25 subjects (six nonsmokers, 11 healthy smokers, and eight COPD subjects FEV1 30–60 %). Six endobronchial biopsies per subject were performed. GCH was measured by measuring mucin volume density (MVD) using stereological techniques on periodic acid fast-Schiff stained samples. We measured the levels of chemokines CXCL8/IL-8, CCL2/MCP-1, CCL7/MCP-3, CCL22/MCD, CCL3/MIP-1α, and CCL4/MIP-1β, and the cytokines IL-1, IL-4, IL-6, IL-9, IL-17, EGF, and vascular endothelial growth factor (VEGF). Differences between groups were assessed using one-way ANOVA, t test, or Chi squared test. Post hoc tests after ANOVA were performed using Bonferroni correction.ResultsMVD was highest in healthy smokers (27.78 ± 10.24 μL/mm2) compared to COPD subjects (16.82 ± 16.29 μL/mm2, p = 0.216) and nonsmokers (3.42 ± 3.07 μL/mm2, p <0.0001). Plasma CXCL8 was highest in healthy smokers (11.05 ± 8.92 pg/mL) compared to nonsmokers (1.20 ± 21.92 pg/mL, p = 0.047) and COPD subjects (6.01 ± 5.90 pg/mL, p = 0.366). CCL22 and CCL4 followed the same trends. There were no significant differences in the other cytokines measured. When the subjects were divided into current smokers (healthy smokers and COPD current smokers) and non/ex-smokers (nonsmokers and COPD ex-smokers), plasma CXCL8, CCL22, CCL4, and MVD were greater in current smokers. No differences in other cytokines were seen. Plasma CXCL8 moderately correlated with MVD (r = 0.552, p = 0.003).DiscussionIn this small cohort, circulating levels of the chemokines CXCL8, CCL4, and CCL22, as well as MVD, attain the highest levels in healthy smokers compared to nonsmokers and COPD subjects. These findings seem to be driven by current smoking and are independent of airflow obstruction.ConclusionsThese data suggest that smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and this correlates significantly with the development of goblet cell hyperplasia.
Highlights
Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH)
These data suggest that smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and this correlates significantly with the development of goblet cell hyperplasia
As previously shown, we found that GCH was greatest in smokers without airflow obstruction compared to COPD subjects and nonsmokers, and that this effect was primarily driven by current smoking [13]
Summary
Chronic Obstructive Pulmonary Disease (COPD) is characterized by lung and systemic inflammation as well as airway goblet cell hyperplasia (GCH). Chronic Obstructive Pulmonary Disease (COPD) is characterized by an abnormal inflammatory response to noxious environmental stimuli in the lung [1]. Persistent lung inflammation leads to the development of emphysema and airway disease, of which goblet cell hyperplasia (GCH) is a crucial component [2]. It has been shown that subjects with more airflow obstruction have a greater burden of mucus in the small airways [4]. A bronchoscopic study in smokers with and without airflow obstruction demonstrated more GCH in the large airways, in those with COPD [5]. There is a large disconnect between symptoms of cough and sputum and mucus burden [6]. The most well characterized pathologic index described by Reid has shown only a weak relationship between chronic bronchitic symptoms [7]
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