title: Plasma Chemokine signature correlates with lung goblet cell hyperplasia in smokers with and without chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Chronic 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  MVD was highest in healthy smokers (27.78 ± 10.24 μL/mm(2)) compared to COPD subjects (16.82 ± 16.29 μL/mm(2), p = 0.216) and nonsmokers (3.42 ± 3.07 μL/mm(2), 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).
  
  
  CONCLUSIONS
  In 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, 3401 North Broad Street, 785 Parkinson Pavilion, Philadelphia, PA, 19140, USA. Victor.kim@tuhs.temple.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Kim
authors.affiliation: Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, PA, USA. cornwell@temple.edu.
authors.forename: William D
authors.initials: WD
authors.lastname: Cornwell
authors.affiliation: Department of Pathology, Temple University School of Medicine, Philadelphia, PA, USA. Michelle.Grant@tuhs.temple.edu.
authors.forename: Michelle
authors.initials: M
authors.lastname: Oros
authors.affiliation: Department of Pathology, Temple University School of Medicine, Philadelphia, PA, USA. Heba.Durra@tuhs.temple.edu.
authors.forename: Heba
authors.initials: H
authors.lastname: Durra
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, 3401 North Broad Street, 785 Parkinson Pavilion, Philadelphia, PA, 19140, USA. Gerard.Criner@tuhs.temple.edu.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Criner
authors.affiliation: Center for Inflammation, Translational and Clinical Lung Research, Temple University School of Medicine, Philadelphia, PA, USA. Thomas.Rogers@temple.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rogers
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018932:Chemokine CCL2 / Q000276:immunology; D054422:Chemokine CCL22 / Q000276:immunology; D054405:Chemokine CCL3 / Q000276:immunology; D054407:Chemokine CCL4 / Q000276:immunology; D054410:Chemokine CCL7 / Q000276:immunology; D018925:Chemokines / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004815:Epidermal Growth Factor / Q000276:immunology; D005260:Female; D020397:Goblet Cells / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D016906:Interleukin-9 / Q000276:immunology; D008168:Lung / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009077:Mucins; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D012907:Smoking / Q000276:immunology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
chemical_list: C111835:CCL2 protein, human; C515482:CCL22 protein, human; C515429:CCL3 protein, human; C066507:CCL4 protein, human; C515450:CCL7 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054422:Chemokine CCL22; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054410:Chemokine CCL7; D018925:Chemokines; D016207:Cytokines; C508598:IL4 protein, human; C508600:IL6 protein, human; C508607:IL9 protein, human; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D016906:Interleukin-9; D009077:Mucins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D015847:Interleukin-4; D004815:Epidermal Growth Factor