Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma

ADAM33

The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 850 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of Chapter 257 is ADAM3

Intersections between pulmonary development and disease

Recent advances in cellular, molecular, and developmental biology have revolutionized our concepts regarding the process of organogenesis that have important implications for our understanding of both lung formation and pulmonary disease pathogenesis. Pulmonary investigators have long debated whether developmental processes are recapitulated during normal repair of the lung or in the setting of chronic pulmonary diseases. Although the cellular events involved in lung morphogenesis and those causing pulmonary disease are likely to include processes that are distinct, there is increasing evidence that the pathogenesis of many lung disorders involves the same genetic machinery that regulates cell growth,specification, and differentiation during normal lung development

Multimorbidity in difficult asthma: the need for personalised and non-pharmacological approaches to address a difficult breathing syndrome

Three to ten percent of people living with asthma have difficult-to-treat asthma that remains poorly controlled despite maximum levels of guideline-based pharmacotherapy. This may result from a combination of multiple adverse health issues including aggravating comorbidities, inadequate treatment, suboptimal inhaler technique and/or poor adherence that may individually or collectively contribute to poor asthma control. Many of these are potentially "treatable traits" that can be pulmonary, extrapulmonary, behavioural or environmental factors. Whilst evidence-based guidelines lead clinicians in pharmacological treatment of pulmonary and many extrapulmonary traits, multiple comorbidities increase the burden of polypharmacy for the patient with asthma. Many of the treatable traits can be addressed with non-pharmacological approaches. In the current healthcare model, these are delivered by separate and often disjointed specialist services. This leaves the patients feeling lost in a fragmented healthcare system where clinical outcomes remain suboptimal even with the best current practice applied in each discipline. Our review aims to address this challenge calling for a paradigm change to conceptualise difficult-to-treat asthma as a multimorbid condition of a "Difficult Breathing Syndrome" that consequently needs a holistic personalised care attitude by combining pharmacotherapy with the non-pharmacological approaches. Therefore, we propose a roadmap for an evidence-based multi-disciplinary stepped care model to deliver this

Rhinovirus-16 induced release of IP-10 and IL-8 is augmented by Th2 cytokines in a pediatric bronchial epithelial cell model

Th2 cytokines increase release of inflammatory cytokines in the presence of rhinovirus infection. This increase is independent of effects of virus replication. Inhibition of the PI3K pathway inhibits IP-10 expression

Contribution of bronchial fibroblasts to the antiviral response in asthma.

Human rhinoviruses (HRV) are a major cause of asthma exacerbations and hospitalization. Studies using primary cultures suggest that this may be due to impaired production of type I and type III IFNs by asthmatic bronchial epithelial cells. Although epithelial cells are the main target for HRV infection, HRV can be detected in the subepithelial layer of bronchial mucosa from infected subjects by in situ hybridization. Therefore, we postulated that submucosal fibroblasts are also involved in the innate antiviral response to HRV infection in asthma. We found that regardless of subject group, bronchial fibroblasts were highly susceptible to RV1b infection. IL-8 and IL-6 were rapidly induced by either HRV or UV-irradiated virus, suggesting that these responses did not require viral replication. In contrast, RANTES expression was dependent on viral replication. Regardless of disease status, fibroblasts did not respond to HRV infection with significant induction of IFN-beta, even though both groups responded to synthetic dsRNA with similar levels of IFN-beta expression. Exogenous IFN-beta was highly protective against viral replication. Our data suggest that fibroblasts respond to HRV with a vigorous proinflammatory response but minimal IFN-beta expression. Their susceptibility to infection may cause them to be a reservoir for HRV replication in the lower airways, especially in asthmatic subjects where there is reduced protection offered by epithelial-derived IFNs. Their ability to support viral replication coupled with their vigorous proinflammatory response following infection may contribute to asthma exacerbations

Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma

AIM: Chronic airway diseases such as asthma are associated with increased production of reactive oxygen species (ROS) and oxidative stress. Endogenous NADPH oxidases are a major source of superoxide in lung, but their underlying role in asthma pathology is poorly understood. We sought to characterize the involvement of NADPH oxidase in allergic asthma by studying the role of CYBA (p22phox) in human asthma and murine house dust mite (HDM)-induced allergic airway inflammation.RESULTS: Increased expression and localisation of p22-PHOX was observed in biopsies of asthmatic patients. HDM treated wild-type mice possessed elevated p22phox expression, corresponded with elevated superoxide production. p22phox knockout (KO) mice did not induce superoxide and were protected against HDM-induced goblet cell hyperplasia and mucus production and HDM-induced airway-hyperreactivity (AHR). IL-13 induced tracheal hyperreactivity and Signal transducer and activator of transcription (STAT)6 phosphorylation was attenuated in the absence of p22phox or catalase pretreatment.INNOVATION: Our study identifies increased expression of p22phox in lungs of asthmatic patients and in experimental model. The induced AHR and mucus hypersecretion is result of an increased ROS from the p22phox dependent NADPH oxidase, which in turn activates STAT6 for the pathological feature of Asthma.CONCLUSIONS: Together with the increased p22phox expression in lungs of asthmatic patients, these findings demonstrate a crucial role of p22phox dependent NADPH oxidase for the development of mucus hypersecretion and AHR in HDM-induced model of asthma. This suggests inhibition of functional NADPH oxidase by selective interference of p22phox might hold promising therapeutic strategy for the management of asthma.</p

Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma

AIM: Chronic airway diseases such as asthma are associated with increased production of reactive oxygen species (ROS) and oxidative stress. Endogenous NADPH oxidases are a major source of superoxide in lung, but their underlying role in asthma pathology is poorly understood. We sought to characterize the involvement of NADPH oxidase in allergic asthma by studying the role of CYBA (p22phox) in human asthma and murine house dust mite (HDM)-induced allergic airway inflammation.RESULTS: Increased expression and localisation of p22-PHOX was observed in biopsies of asthmatic patients. HDM treated wild-type mice possessed elevated p22phox expression, corresponded with elevated superoxide production. p22phox knockout (KO) mice did not induce superoxide and were protected against HDM-induced goblet cell hyperplasia and mucus production and HDM-induced airway-hyperreactivity (AHR). IL-13 induced tracheal hyperreactivity and Signal transducer and activator of transcription (STAT)6 phosphorylation was attenuated in the absence of p22phox or catalase pretreatment.INNOVATION: Our study identifies increased expression of p22phox in lungs of asthmatic patients and in experimental model. The induced AHR and mucus hypersecretion is result of an increased ROS from the p22phox dependent NADPH oxidase, which in turn activates STAT6 for the pathological feature of Asthma.CONCLUSIONS: Together with the increased p22phox expression in lungs of asthmatic patients, these findings demonstrate a crucial role of p22phox dependent NADPH oxidase for the development of mucus hypersecretion and AHR in HDM-induced model of asthma. This suggests inhibition of functional NADPH oxidase by selective interference of p22phox might hold promising therapeutic strategy for the management of asthma.</p