title: Association of Lung Inflammatory Cells with Small Airways Function and Exhaled Breath Markers in Smokers - Is There a Specific Role for Mast Cells?
abstract: BACKGROUND
  Smoking is associated with a mixed inflammatory infiltrate in the airways. We evaluated whether airway inflammation in smokers is related to lung function parameters and inflammatory markers in exhaled breath.
  
  
  METHODS
  Thirty-seven smokers undergoing lung resection for primary lung cancer were assessed pre-operatively by lung function testing including single-breath-nitrogen washout test (sb-N2-test), measurement of fractional exhaled nitric oxide (FeNO) and pH/8-isoprostane in exhaled breath condensate (EBC). Lung tissue sections containing cancer-free large (LA) and small airways (SA) were stained for inflammatory cells. Mucosal (MCT) respectively connective tissue mast cells (MCTC) and interleukin-17A (IL-17A) expression by mast cells was analysed using a double-staining protocol.
  
  
  RESULTS
  The median number of neutrophils, macrophages and mast cells infiltrating the lamina propria and adventitia of SA was higher than in LA. Both MCTC and MCT were higher in the lamina propria of SA compared to LA (MCTC: 49 vs. 27.4 cells/mm2; MCT: 162.5 vs. 35.4 cells/mm2; P<0.005 for both instances). IL-17A expression was predominantly detected in MCTC of LA. Significant correlations were found for the slope of phase III % pred. of the sb-N2-test (rs= -0.39), for the FEV1% pred. (rs= 0.37) and for FEV1/FVC ratio (rs=0.38) with MCT in SA (P<0.05 for all instances). 8-isoprostane concentration correlated with the mast cells in the SA (rs=0.44), there was no correlation for pH or FeNO with cellular distribution in SA.
  
  
  CONCLUSIONS
  Neutrophils, macrophages and mast cells are more prominent in the SA indicating that these cells are involved in the development of small airway dysfunction in smokers. Among these cell types, the best correlation was found for mast cells with lung function parameters and inflammatory markers in exhaled breath. Furthermore, the observed predominant expression of IL-17A in mast cells warrants further investigation to elucidate their role in smoking-induced lung injury, despite the lack of correlation with lung function and exhaled breath parameters.
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nussbaumer-Ochsner
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.affiliation: Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Ferraz da Silva
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: van Schadewijk
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: de Jeu
authors.affiliation: Department of Pathology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Frans A
authors.initials: FA
authors.lastname: Prins
authors.affiliation: Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil.
authors.forename: Thais
authors.initials: T
authors.lastname: Mauad
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands; Center for Pneumology and Thoracic Surgery, Grosshansdorf Hospital, Grosshansdorf, Germany.
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.affiliation: Department of Pulmonology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D012907:Smoking / Q000378:metabolism / Q000473:pathology*
chemical_list: D020381:Interleukin-17; D009569:Nitric Oxide