Plasma Chemokine signature correlates with lung goblet cell hyperplasia in smokers with and without chronic obstructive pulmonary disease

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.

Decreased plasma epidermal growth factor (EGF) levels in patients with severe chronic obstructive pulmonary disease

“…EGF also activates fibroblasts and stimulates their proliferation (20), however, cigarette smoke, in the absence of the clinical presentation of COPD, it has been implicated in mucus production in airways via activation of the EGFR (24,25). Smoking upregulates a systemic pattern of neutrophil and macrophage chemoattractant expression, and it was correlated significantly with the development of goblet cell hyperplasia (26).…”

PTGDR gene expression and response to dexamethasone treatment in an in vitro model

“…In addition, the presence of different PTGDR promoter haplotypes appears to cause different response after dexamethasone treatment. These preliminary data suggest that cells harbouring the wild-type haplotype have a better response to glucocorticoid showing a more pronounced decrease of proinflammatory cytokines, including cytokines and chemokines associated with asthma and Th2 lung inflammation, as IP-10 and RANTES [ 51 , 52 ], MIP-1β[ 53 ], IL-6, IL-8 [ 54 ], and eotaxin [ 55 , 56 ].…”

Chemokines in COPD: From Implication to Therapeutic Use

“…First, many chemokines seem to be associated with smoking status rather than the airflow obstruction characteristic of COPD [82]. For instance, a recent study found that circulating levels of the chemokines CXCL8, CCL4, and CCL22 attain the highest levels in healthy smokers compared to nonsmokers and COPD subjects [91]. The same finding has been observed with CCL17 which has increased mRNA levels in pulmonary cells and in the broncho-alveolar lung fluid (BALF) of COPD patients compared to nonsmokers controls but not compared to current or ex-smokers [92].…”