Effect of long-term corticosteroid treatment on microRNA and gene-expression profiles in Chronic Obstructive Pulmonary Disease
- Alen Faiz1,2,3,4,*,
- Katrina Steiling5,
- Mirjam P. Roffel2,3,
- Dirkje S. Postma1,3,
- Avrum Spira5,
- Marc E. Lenburg5,
- Malte Borggrewe2,
- Tim R. Eijgenraam2,
- Marnix R. Jonker2,
- Gerard H. Koppelman3,6,
- Simon D. Pouwels1,2,3,
- Gang Liu5,
- Yuriy O. Alekseyev7,
- Stephen Lam8,
- Pieter S. Hiemstra9,
- Peter J. Sterk10,
- Wim Timens2,3,
- Corry-Anke Brandsma2,3,
- Irene H. Heijink1,2,3,‡ and
- Maarten van den Berge1,3,‡
- 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands
- 2University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, Groningen, The Netherlands
- 3University of Groningen, University Medical Center Groningen, GRIAC (Groningen Research Institute for Asthma and COPD), Groningen, The Netherlands
- 4University of Technology Sydney, Faculty of Science, Respiratory Bioinformatics and Molecular Biology (RBMB), Ultimo, NSW, Australia
- 5Boston University School of Medicine, Division of Computational Biomedicine, Department of Medicine, Boston, Massachusetts, USA
- 6University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen, The Netherlands
- 7Boston University School of Medicine, Department of Pathology and Laboratory Medicine, Boston, Massachusetts, USA
- 8Cancer Imaging, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
- 9Leiden University Medical Center, Department of Pulmonary Diseases, Leiden, The Netherlands
- 10University of Amsterdam, Department of Respiratory Medicine, F5-259, Academic Medical Centre, Amsterdam, The Netherlands
- Alen Faiz. E-mail: a.faiz{at}umcg.nl
‡ Shared last authorship; both authors contributed equally
Abstract
To investigate whether microRNA (miRNA) expression is modulated by inhaled corticosteroid (ICS) treatment, we performed genome-wide miRNA analysis on bronchial biopsies of 69 moderate/severe COPD patients at baseline and after 6- and 30-month treatment with the ICS fluticasone propionate (FP) 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 4 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 (NF)-κB. Collectively, we identified miR-320d as a novel mediator of ICS, regulating the pro-inflammatory response of the airway epithelium.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Alen Faiz
Conflict of interest: Dr. Steiling has a patent “Biomarkers of COPD disease activity” pending.
Conflict of interest: P. Roffel
Conflict of interest: S. Postma
Conflict of interest: Avrum Spira
Conflict of interest: E. Lenburg
Conflict of interest: Malte Borggrewe
Conflict of interest: R. Eijgenraam
Conflict of interest: R. Jonker
Conflict of interest: H. Koppelman
Conflict of interest: D. Pouwels
Conflict of interest: Gang Liu
Conflict of interest: Dr. Alekseyev has nothing to disclose.
Conflict of interest: Stephen Lam
Conflict of interest: S. Hiemstra
Conflict of interest: Dr. Sterk reports grants from GlaxoSmithKline, grants from Dutch Government, during the conduct of the study.
Conflict of interest: Wim Timens
Conflict of interest: Corry-Anke Brandsma
Conflict of interest: H. Heijink
Conflict of interest: Maarten van den Berge
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