A Life Course Approach to Investigating Asthma Pathogenesis and Progression

哮喘是英国最常见的慢性肺部疾病。它影响到所有年龄段，并对生活质量、学校教育和工作产生重大影响。对于大多数人来说，由于疾病的多变性质，它需要终身药物治疗和不确定性。人们很少知道这些因素如何在疾病早期引发疾病或对疾病的整个生命过程产生影响。这项计划集中研究哮喘的生命过程，重点研究可能导致疾病持续和发展的潜在机制，以及不同环境因素如何影响。我们的研究重点是人类哮喘，涉及对呼吸道进行采样，以评估正在进行的组织事件，并获得可在不同暴露条件下在实验室进行研究的呼吸道细胞。我们认为，呼吸道衬里(上皮)在与环境相互作用中发挥着重要作用，在哮喘中，它表达的信号促进了呼吸道内的异常炎症，并诱导了结构变化(疤痕形成)，从而改变了它们的灵活性。我们将这种上皮与更深层的气道壁结构之间的动态相互作用称为上皮间充质营养单位(EMTU)。我们的研究重点是了解这种EMTU是如何在不同严重程度和疾病阶段的哮喘中被激活的。认识到大多数哮喘都起源于生命的最初几年，在儿童和青春期经历了重大变化，其中一半以上的人长大了？随着他们疾病的发生并采用在一些成年人中变得不可逆转的特征，我们分3个阶段制定了我们的5年计划：(I)在幼儿中，当疾病发生时，我们将在有无病毒、变应原和烟草烟雾暴露的情况下使用我们的细胞培养系统，以寻求EMTU中上皮细胞与潜在细胞沟通的方式的差异；ii)在我们鬼魂岛的青少年队列中，从出生到18岁，我们将广泛地描述与哮喘有关的EMTU的激活情况，我们将评估持续哮喘患者和已长大的青少年EMTU的激活情况。(Iii)在确诊为哮喘的成人中，我们确定疤痕如何影响气道壁的僵硬，以及反复气道狭窄是否会导致此类哮喘的治疗反应丧失，并可解释这种哮喘的治疗反应丧失。这项研究将在疾病预防和治疗中确定迫切需要的新靶点。

Asthma is the commonest chronic lung disease in the UK. It affects all age groups and significantly impacts on quality of life, schooling and work. For most it requires lifelong treatment with drugs and uncertainty, due to the variable nature of the disease. Little is known how factors initiate the disease in early life or impact over the life course of the disease. This programme is centred on studying the life course of asthma, focusing on underlying mechanisms that may lead to disease persistence and progression and how different environmental factors exert influence.Our research focuses on the human asthma and involves sampling the airways to evaluate on-going tissue events and to obtain airway cells that can be studied in the laboratory under different conditions of exposure. We believe that the airways lining (epithelium) plays a major role in interacting with the environment and, in asthma, expresses signals that promote abnormal inflammation within the airways and induce structural changes (scarring) that alters their flexibility. We have called this dynamic interaction between the epithelium and the deeper airway wall structures the Epithelial Mesenchymal Trophic Unit (EMTU). Our research focuses on understanding how this EMTU is activated in asthma of differing severity and stages of disease. Recognising that most asthma has its origin in the first few years of life, undergoes major changes during childhood and adolescence in which over half ?grow out? of their diseases and adopts characteristics of becoming irreversible in some adults, we have constructed our 5 year programme in 3 stages: (i) In young children at the onset of disease we will use our cell culture systems in the presence and absence of virus, allergen and tobacco smoke exposure to seek differences in the way the epithelium communicates with underlying cells in the EMTU; ii) In teenagers from our Isle of Wight cohort, that has been extensively characterised in relationship to asthma from birth to the age of 18 years, we will assess activation of the EMTU in those with persistent asthma and those who have ?grown out? of asthma; and (iii) In adults with established asthma we determine how the scarring affects the stiffness of the airway wall and whether repeated airway narrowing contributes to and can account for the loss of treatment response in such asthmatics.This research will identify much needed new targets in disease prevention and treatment high up in the causal disease pathways.