Abstract
Chronic cough is associated with airway inflammation and remodelling. Abnormal airway smooth muscle cell (ASMC) function may underlie mechanisms of chronic cough. Our objective was to examine the transcriptome and focused secretome of ASMCs from chronic cough patients and healthy non-cough volunteers. ASMC gene expression profiling was performed at baseline and/or after stimulation with polyinosinic:polycytidylic acid (poly(I:C)) to mimic viral infection. Supernatants were collected for multiplex analysis. Our results showed no significant differentially expressed genes (DEGs, false discovery rate (FDR) <0.05) between chronic cough and healthy non-cough ASMCs at baseline. Poly(I:C) stimulation resulted in 212 DEGs (>1.5 fold-change, FDR <0.05) in ASMCs from chronic cough patients compared with 1674 DEGs in healthy non-cough volunteers. The top up-regulated genes included chemokine (C–X–C motif) ligand (CXCL) 11 (CXCL11), CXCL10, chemokine (C–C motif) ligand (CCL) 5 (CCL5) and interferon-induced protein 44 like (IFI44L) corresponding with inflammation and innate immune response pathways. ASMCs from cough subjects had enhanced activation of viral response pathways in response to poly(I:C) compared with healthy non-cough subjects, reduced activation of pathways involved in chronic inflammation and equivalent activation of neuroregulatory genes. The poly(I:C)-induced release of inflammatory mediators, including CXCL8, interleukin (IL)-6 and CXCL1, from ASMCs from cough patients was significantly impaired compared with healthy non-cough subjects. Addition of fluticasone propionate (FP) to poly(I:C)-treated ASMCs resulted in greater gene expression changes in healthy non-cough ASMCs. FP had a differential effect on poly(I:C)-induced mediator release between chronic cough and healthy non-cough volunteers. In conclusion, altered innate immune and inflammatory gene profiles within ASMCs, rather than infiltrating cells or nerves, may drive the cough response following respiratory viral infection.
Highlights
Chronic cough defined as the cough lasting for more than 8 weeks is a common clinical problem present in a proportion of the population [1,2]
There was a small but significant (P
We report that ASMCs from chronic cough patients have an enhanced infection response and a reduced innate immune and inflammatory response to poly(I:C) stimulation compared with cells from healthy non-cough volunteers
Summary
Chronic cough defined as the cough lasting for more than 8 weeks is a common clinical problem present in a proportion of the population [1,2]. Cough variant asthma and eosinophilic bronchitis are two common causes of chronic cough associated with eosinophilia that respond to anti-inflammatory corticosteroids [5,6]. Some forms of chronic cough in which no identifiable cause is found, termed as idiopathic cough, can be associated with inflammatory and airway wall remodelling features in the airways submucosa including an increase in mast cells, goblet cell hyperplasia, increased blood vessels and airway smooth muscle hypertrophy and hyperplasia [7]. Elevated levels of inflammatory mediators including chemokine (C–X–C motif) ligand (CXCL) 8 (CXCL8), tumour necrosis factor α (TNFα) and myeloperoxidase, lipids such as prostaglandin c 2017 The Author(s).
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