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Asthma management guidelines recommend adding a long-acting β2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12–80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61–62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13–1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05–1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.

The aim was to investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatmentWe performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe chronic obstructive pulmonary disease (COPD) patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate or placebo. The effect of ICS on miRNA expression was validated in differentiated primary bronchial epithelial cultures, and functional studies were conducted in BEAS-2B cells. MiRNAs affected by ICS and their predicted targets were compared to an independent miRNA dataset of bronchial brushings from COPD patients and healthy controls.Treatment with ICS for both 6 and 30 months significantly altered the expression of four miRNAs, including miR-320d, which was increased during ICS treatment compared with placebo. The ICS-induced increase of miR-320d was confirmed in primary airway epithelial cells. MiR-320d negatively correlated targets were enriched for pro-inflammatory genes and were increased in the bronchial brushes of patients with lower lung function in the independent dataset. Overexpression of miR-320d in BEAS-2B cells dampened cigarette smoke extract-induced pro-inflammatory activity via inhibition of nuclear factor-κB.Collectively, we identified miR-320d as a novel mediator of ICS, regulating the pro-inflammatory response of the airway epithelium., Competing Interests: Conflict of interest: A. Faiz has nothing to disclose. Conflict of interest: K. Steiling has a patent “Biomarkers of COPD disease activity” pending. Conflict of interest: M.P. Roffel has nothing to disclose. Conflict of interest: D.S. Postma reports institutional grants from AstraZeneca, Chiesi, Genentec, GSK and Roche, and fees for consultancy from Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. Conflict of interest: A. Spira has nothing to disclose. Conflict of interest: M.E. Lenburg has nothing to disclose. Conflict of interest: M. Borggrewe has nothing to disclose. Conflict of interest: T.R. Eijgenraam has nothing to disclose. Conflict of interest: M.R. Jonker has nothing to disclose. Conflict of interest: G.H. Koppelman reports institutional grants from Netherlands Lung Foundation, Ubbo Emmius Foundation, TEVA Pharmaceuticals and Stichting Astma Bestrijding, outside the submitted work Conflict of interest: S.D. Pouwels has nothing to disclose. Conflict of interest: G. Liu has nothing to disclose. Conflict of interest: Y.O. Alekseyev has nothing to disclose. Conflict of interest: S. Lam has nothing to disclose. Conflict of interest: P.S. Hiemstra reports grants from Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, University of Groningen, Leiden University Medical Center and GlaxoSmithKline, during the conduct of the study. Conflict of interest: P.J. Sterk reports grants from GlaxoSmithKline and the Dutch Government, during the conduct of the study. Conflict of interest: W. Timens reports personal fees for consultancy from Pfizer and Merck Sharp Dohme, personal fees for lecturing from GSK, Lilly Oncology and Chiesi, personal fees for lecturing, consultancy and travel from Roche Diagnostics/Ventana, travel costs from Biotest, personal fees for lecturing and consultancy Novartis, and grants from the Dutch Asthma Fund, outside the submitted work. Conflict of interest: C-A. Brandsma has nothing to disclose. Conflict of interest: I.H. Heijink has nothing to disclose. Conflict of interest: M. van den Berge reports institutional research grants from Chiesi, Teva Pharma and AstraZeneca, outside the submitted work., (Copyright ©ERS 2019.)

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC -related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1 , as potential key miRNA-mRNA networks regulating CMH in COPD., Competing Interests: Conflict of interest: W. Timens reports receiving an unrestricted grant from Merck to his institution during the conduct of the study; a consultancy fee to his institution from Pfizer, lecture fees to his institution from GSK, Chiesi and Boehringer Ingelheim, lecture and consultancy fees and travel costs to his institution from Roche Diagnostics/Ventana, a grant from the Dutch Asthma Fund, travel costs to his institution from Biotest, consultancy and course fees to his institution from Merck Sharp Dohme, lecture/course and consultancy fees to his institution from Novartis, personal fees from Lilly Oncology, outside the submitted work. Conflict of interest: R. Gosens reports receiving grants from Boehringer Ingelheim, Chiesi Farmaceutici and Aquilo, is a cofounder of Aquilo, and reports receiving grants from and has served on an advisory board for Holaira, outside the submitted work. Conflict of interest: P. Hiemstra reports receiving grants from Galapagos N.V. and Boehringer Ingelheim, outside the submitted work. Conflict of interest: A. Spira has acted as a consultant for and holds stock options in Veracyte Inc, and has acted as a consultant for Janssen Pharma, outside the submitted work. Conflict of interest: D.S. Postma reports that the University of Groningen has received money regarding a grant for research from AstraZeneca, Chiesi, Genentech, GSK and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. Conflict of interest: G.W. Tew is an employee of Genentech Inc. Conflict of interest: M.A. Grimbaldeston is an employee of Genentech Inc. Conflict of interest: M. van den Berge reports grants paid to the University of Groningen from AstraZeneca, TEVA, GSK and Chiesi, outside the submitted work., (Copyright ©ERS 2018.)

Interleukin-1 receptor-like 1 ( IL1RL1 ) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10 -16 ) and serum IL1RL1-a levels (p=2.8×10 -56 ). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1- methylation CpG sites nor IL1RL1-a levels are associated with asthma., Competing Interests: Conflict of interest: J. Bousquet has received personal fees for acting on scientific and advisory boards from Almirall, Meda, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach; and personal fees for lecturing from Almirall, AstraZeneca, Chiesi, GSK, Meda, Menarini, Merck, MSD, Novartis, Sanofi-Aventis, Takeda, Teva and Uriach, outside the submitted work. Conflict of interest: R.J.P. van der Valk received a grant from the Dutch Lung Foundation during the conduct of the study; and is a Dutch Medical Affairs employee of GlaxoSmithKline (since June 2015), but does not hold stocks and is not involved in conducting any R&D activities for GlaxoSmithKline. Conflict of interest: M.C. Nawijn received a supporting grant to his institution for the submitted work from the Lung Foundation Netherlands during the conduct of the study. Conflict of interest: S. Guerra received a grant from European Commission's Seventh Framework Programme during the conduct of the study. Conflict of interest: D.S. Postma: The University of Groningen received grants for research from AstraZeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. Conflict of interest: G.H. Koppelman has received institutional grants from the Netherlands Lung Foundation, Ubbo Emmius Foundation and the European Commission during the conduct of the study; and grants from the Netherlands Lung Foundation, TEVA (the Netherlands) and Stichting Astma Bestrijding outside the submitted work., (Copyright ©ERS 2018.)

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial-mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene.Our results suggest that induction of miR-146a-5p is involved in epithelial-fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Wingless/integrase-1 (WNT) signalling is associated with lung inflammation and repair, but its role in chronic obstructive pulmonary disease (COPD) pathogenesis is unclear. We investigated whether cigarette smoke-induced dysregulation of WNT-5B contributes to airway remodelling in COPD.We analysed WNT-5B protein expression in the lung tissue of COPD patients and (non)smoking controls, and investigated the effects of cigarette smoke exposure on WNT-5B expression in COPD and control-derived primary bronchial epithelial cells (PBECs). Additionally, we studied downstream effects of WNT-5B on remodelling related genes fibronectin, matrix metalloproteinase (MMP)-2, MMP-9 and SnaiI in BEAS-2B and air-liquid interface (ALI)-cultured PBECs.We observed that airway epithelial WNT-5B expression is significantly higher in lung tissue from COPD patients than controls. Cigarette smoke extract significantly increased mRNA expression of WNT-5B in COPD, but not control-derived PBECs. Exogenously added WNT-5B augmented the expression of remodelling related genes in BEAS-2B cells, which was mediated by transforming growth factor (TGF)-β/Smad3 signalling. In addition, WNT-5B upregulated the expression of these genes in ALI-cultured PBECs, particularly PBECs from COPD patients.Together, our results provide evidence that exaggerated WNT-5B expression upon cigarette smoke exposure in the bronchial epithelium of COPD patients leads to TGF-β/Smad3-dependent expression of genes related to airway remodelling., (Copyright ©ERS 2016.)

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial-mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial-fibroblast interaction in COPD., (Copyright ©ERS 2016.)