Bronchial thermoplasty (BT) is to date the only therapy that provides a lasting reduction in airway wall remodelling. However, the mechanism of action of BT is not well understood. This study aimed to characterise the changes of remodelling regulating signalling pathways by BT in asthma.Bronchoalveolar lavage fluid (BALF) was obtained from eight patients with severe asthma before and after BT. Primary bronchial epithelial cells were isolated from 23 patients before (n=66) and after (n=62) BT. Epithelial cell culture supernatant (Epi.S) was collected and applied to primary fibroblasts.Epithelial cells obtained from asthma patients after BT proliferated significantly faster compared with epithelial cells obtained before BT. In airway fibroblasts, BALF or Epi.S obtained before BT increased CCAAT enhancer-binding protein-β (C/EBPβ) expression, thereby downregulating microRNA-19a. This upregulated extracellular signal-regulated kinase-1/2 (ERK1/2) expression, protein arginine methyltransferase-1 (PRMT1) expression, cell proliferation and mitochondrial mass. BALF or Epi.S obtained after BT reduced the expression of C/EBPβ, ERK1/2, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), PRMT1 and mitochondrial mass in airway fibroblasts. Proteome and transcriptome analyses indicated that epithelial cell-derived heat shock protein-60 (HSP60) is the main mediator of BT effects on fibroblasts. Further analysis suggested that HSP60 regulated PRMT1 expression, which was responsible for the increased mitochondrial mass and α-smooth muscle actin expression by asthmatic fibroblasts. These effects were ablated after BT. These results imply that BT reduces fibroblast remodelling through modifying the function of epithelial cells, especially by reducing HSP60 secretion and subsequent signalling pathways that regulate PRMT1 expression.We therefore hypothesise that BT decreases airway remodelling by blocking epithelium-derived HSP60 secretion and PRMT1 in fibroblasts.

Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases that share some common characteristics. Asthma is associated with airway hyperresponsiveness, airway inflammation and airflow limitation that is reversible [1]. COPD is characterised by persistent and progressive airflow limitation and airway inflammation [2]. In recent years, there has been an ongoing discussion of whether asthma and COPD are different diseases, since a significant proportion of patients with symptoms of obstructive lung disease has features of both asthma and COPD [3-5]. In this respect, the most clinically significant phenotypes are COPD patients with asthmatic features and asthmatic patients that smoke. These patients may necessitate different therapeutic approaches and, therefore, there is a great need for diagnostic criteria that would allow proper diagnosis and treatment [6, 7]. Histological analysis has been previously suggested as a tool to identify and understand overlapping clinical and physiological phenotypes, thereby helping to better design treatments and plan long-term management [8]. However, there are few studies that have examined the histological patterns of patients who may be characterised as having asthma-COPD overlap. The present study is a pilot to provide data to inform the design and size of a study to test whether there are consistent histological differences between COPD patients with asthmatic features and asthma patients who have smoked. We included patients drawn from a cohort of COPD patients (total n=147) who underwent diagnostic bronchoscopy for clinical indications such as coin lesions (27%), evaluation of bronchoscopical or surgical low volume reduction procedures (25%), infiltrates (16%) and haemoptysis (8%). COPD patients had an average forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio post-bronchodilation of 0.4 (range 0.3-0.5) and a smoking history of 43 pack-years (range 30-60). We also included a cohort of asthma patients (total n=19), with severe to very severe disease, that underwent bronchial thermoplasty. Diagnosis of COPD and asthma was based on European Respiratory Society/American Thoracic Society guidelines, according to Global Initiative for Chronic Obstructive Lung Disease and Global Initiative for Asthma criteria.

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