S86 Extracellular matrix deposited by asthmatic human airway smooth muscle cells enhances basal activation of tgfβ

Abstract

Results Fifty two patients completed the BCKQ questionnaire: 36 conventional PR programme [20 male, MRC 3 (IQR 2-4), age 67 (±8.5) years, BMI 30 (±6.6) kg/m 2 , FEV 1 (% predicted) 53 (±21), pre ISWT 280 m (±163), pre HADS anxiety 6.6 (±4.8). pre PRAISE 45 (±8.4)] and 16 online [14 male, MRC 3 (IQR 2-4), age 67 (±7.4) years, BMI 25 (±5.0) kg/m 2 , FEV 1 (% predicted) 47 (±27), pre ISWT 365 m (±201), pre HADS anxiety 7.5 (±5.1),pre PRAISE 49 (±7.9)]. There were no significant differences in baseline characteristics. A statistically significant difference was seen in knowledge within each group following either the conventional PR programme (change=5 points, p£0.001) or the web programme (change=11 points, p£0.001). The change in scores between the groups was also significantly different (p£0.01) in favour of the web-based programme (Table 1). Discussion Patients are able to gain improvements in knowledge around their condition using a website programme as an alternative to the traditional spoken sessions in a PR programme. Rationale Severe corticosteroid refractory asthma is a significant unmet medical need. It accounts for 10% of the asthma population and 50% of the health economic burden. Recent understanding of asthma heterogeneity has evolved beyond clinical characteristics, allowing definition of distinct disease phenotypes such as those defined by levels of Type 2 inflammation (Type-2 high 'eosinophilic' disease and Type-2 low 'neutrophilic' disease). However, a recent study using dupilumab (an antibody that blocks the common IL-4 and IL-13 receptor chain, IL-4Ra) as an add-on therapy in adults with uncontrolled persistent asthma showed efficacy irrespective of baseline eosinophil count (Wenzel et al, Lancet 2016). The aim of this work was to use IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms. Methods IL-13 expression in the lungs was induced using Doxycycline (DOX) in Ccsp-rtTA/Otet-Il-13 double-transgenic (Ccsp/Il-13) mice. Littermate control single transgenic mice also received DOX. Where indicated, mice received daily intra-peritoneal injections of 3 mg/kg Dexamethasone (Dex) for 3-7 days and control mice received saline. Methacholine challenge and lung function measurements were performed and lungs harvested for mRNA analysis and immunohistochemistry (IHC). BALF was obtained for ELISA and differential cell counts. Results Compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and IHC revealed increased bronchial smooth muscle and goblet cell metaplasia. The BALF of these mice contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes (Il-13, Eotaxin, Muc5ac, Periostin and SerpinB2) as well as genes more characteristic of Th17 responses (Cxcl1/Kc, Cxcl2 and Csf3) were significantly elevated. Treatment with Dex did not abrogate AHR, even though eosinophilia...