Abstract
BackgroundMyeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. Effects of inhaled corticosteroids (ICS) on airway DCs in smokers are unknown.MethodsIn this randomized, double-blind, placebo-controlled clinical trial, 45 active cigarette smokers inhaled placebo, fluticasone or fluticasone plus salmeterol twice daily for 4 weeks. Bronchoalveolar lavage fluid DCs were analyzed using four-color flow cytometry before and after the inhalation period. In addition, fluticasone effects were tested on T-cell proliferation in co-cultures with blood myeloid DCs from smokers.ResultsInhalation of fluticasone plus salmeterol, but not fluticasone alone or placebo, reduced endobronchial concentrations of myeloid DCs (median decrease: 24%), macrophages (median decrease: 26%) and neutrophils (median decrease: 76%). In contrast, fluticasone reduced plasmacytoid DC concentrations independently of salmeterol. There were no changes in the expression of function-associated surface molecules on myeloid DC (such as CD1a, Langerin, BDCA-1, CD83 or CCR5) in all groups after treatment. Fluticasone (either alone or in combination with salmeterol) suppressed T-cell proliferation in co-cultures with blood myeloid DCs from smokers.ConclusionsResistance to ICS monotherapy in smokers might in part be due to lacking effects on airway myeloid DCs, whereas the increased risk for infections during ICS therapy could be attributable to a reduction in plasmacytoid DCs. Combination therapy of fluticasone with salmeterol is associated with a reduction in airway myeloid DCs, but also airway macrophages and neutrophils.Trial registrationRegistered at ClinicalTrials.gov (identifier: NCT00908362) and the European Clinical Trial Database, EudraCT (identifier: 2009-009459-40).
Highlights
Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections
Airway Myeloid dendritic cell (mDC) of smokers are characterised by changes in function-associated surface molecules, such as an increased expression of the co-stimulatory molecules CD80 and CD86, and an increased expression of antigen recognition receptors such as Blood dendritic cell antigen (BDCA)-1 (CD1c) and Macrophage mannose receptor (MMR) (Macrophage Mannose Receptor) [9]
Smoke-related lung diseases such as chronic obstructive pulmonary disease (COPD) and Pulmonary Langerhans Cell Histiocytosis (PLCH) are accompanied by a local accumulation of DCs in the lungs which exceeds DC numbers in smoking controls [1,10,11,12]
Summary
Myeloid Dendritic cells are key drivers of inflammation in smoke-related lung diseases, whereas plasmacytoid DCs play a crucial role in the defense against infections. There is a substantial body of evidence that corticosteroids influence airway DCs in patients with allergic asthma and allergic rhinitis [14,15,16], there is currently no information on the effect of ICS on airway DCs in cigarette smokers with or without smokerelated lung diseases. It was the aim of this trial to investigate the influence of ICS inhalation on airway DCs in smokers for the first time. Using an established flow cytometric method to analyze DCs in human bronchoalveolar lavage (BAL) fluid [17,18,19], we measured airway DCs in smokers prior to and after 4 weeks of inhalation of fluticasone, and compared the findings with the effects of placebo treatment and of combination therapy (fluticasone plus salmeterol), in a randomized, doubleblind, placebo-controlled clinical trial
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