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。它影响到所有年龄组，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，由于疾病的可变性质，它需要终身药物治疗和不确定性。很少有人知道这些因素如何在生命早期引发疾病或影响疾病的生命过程。该项目的重点是研究哮喘的生命过程，重点是可能导致疾病持续和发展的潜在机制，以及不同的环境因素如何发挥影响。我们的研究重点是人类哮喘，包括采样气道以评估正在进行的组织事件，并获得气道细胞，可以在实验室中在不同的暴露条件下进行研究。我们认为，气道衬里（上皮）在与环境的相互作用中起着重要作用，在哮喘中，表达促进气道内异常炎症的信号，并诱导改变其灵活性的结构变化（瘢痕形成）。我们将上皮和更深的气道壁结构之间的这种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EMTU如何在不同严重程度和疾病阶段的哮喘中被激活。认识到大多数哮喘起源于生命的最初几年，在儿童和青春期经历了重大变化，其中超过一半？长大了吗由于他们的疾病在一些成年人中具有不可逆转的特征，我们已将我们的5年计划分为3个阶段：（i）对于幼儿，在疾病发作时，我们将在存在和不存在病毒、过敏原和烟草烟雾的情况下使用我们的细胞培养系统暴露于烟草烟雾中，以寻找上皮与EMTU中底层细胞通讯方式的差异; ii）在我们的怀特岛队列的青少年中，从出生到18岁，已经广泛表征了与哮喘的关系，我们将评估持续性哮喘患者和患有哮喘的患者的EMTU激活情况。长大了吗哮喘;以及（iii）在已确诊的成人哮喘患者中，我们确定瘢痕形成如何影响气道壁的硬度，以及反复气道狭窄是否有助于并可以解释此类哮喘患者治疗反应的丧失。

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.