Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved.This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling.We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin mouse model of asthma.These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.
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...
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