Molecular mechanisms underlying the development and propagation of preschool wheeze and asthma: the role of interleukin (IL)-33 and activin A

研究背景：虽然大约40%的5岁以下儿童有喘息症状，但大多数儿童长大后症状会消失，只有部分喘息者（约三分之一）在学龄时患上哮喘。我们知道，患有哮喘的儿童很早就会在1到3岁之间的肺部管道（气道）上出现损伤和疤痕，这种情况至少会持续到成年早期。决定学龄前儿童患哮喘的因素包括遗传易感性、早期过敏的发展以及早期肺部感染，尤其是病毒感染。我们无法预测哪些学龄前喘息者会患上哮喘，重要的是，没有药物可以阻止儿童肺功能下降，减少气道瘢痕和损伤。对非常年幼的儿童进行肺疤痕的测量是困难的，因为这需要在全身麻醉期间从肺部采集样本。我们已经开发了一种新的新生小鼠模型来模拟由过敏引起的幼儿早期喘息如何导致学龄哮喘。我们用室内尘螨引起老鼠哮喘。到目前为止，我们已经证明了两种化学物质在引起这种过敏性哮喘方面似乎非常重要。它们被称为白细胞介素(IL)-33和激活素。我们认为，这些新分子的作用可以被阻断，作为一种治疗方法，阻止学龄前哮喘的发展。然而，我们还没有在这个模型中探索病毒感染的影响，关键的是，正如发生在幼儿身上的那样，我们还没有在我们的小鼠模型中研究病毒和过敏的相互作用。目的和目的：因此，本项目的目的是利用引起幼儿喘息的两种病毒，制作一种病毒性肺部感染的新生小鼠模型。然后我们会研究在过敏性哮喘模型中发现的重要分子的产生在单独的病毒感染模型中，以及当病毒感染和室内尘螨一起使用时。我们认为，这些分子在仍在发病的年轻老鼠和已经完全发病的年老老鼠身上具有不同的重要性。一旦我们确定了与病毒引起的疾病、过敏引起的疾病以及两者兼而有之的重要分子，我们将在患有严重症状的儿童样本中确认动物实验的结果。在布朗普顿医院，我们开发了一个项目，使用一种特殊的相机（支气管镜）来观察患有严重喘息或哮喘的儿童的肺部，以帮助找出他们的症状如此严重的原因。此外，如果孩子的父母同意，我们得到伦理委员会的许可，可以使用临床报告后剩余的多余样本进行研究。我们将检查血液样本、呼吸道清洗和呼吸道组织切片，并将仅患有病毒感染的学龄前儿童、患有和不患有病毒的学龄前儿童、患有哮喘的学龄儿童进行比较。样本太小了，我们需要进行有针对性的测量，因此需要动物模型来指导我们哪些分子最有希望。我们将确定至少2个新分子（IL-33和激活素）在学龄前喘息哮喘发展中的作用。通过比较学龄前儿童的哮喘分子和年龄较大的哮喘儿童的分子，我们将能够确定，与年龄较大的哮喘儿童相比，阻断其中一种或另一种分子是否更适合治疗年幼的儿童，当他们患有哮喘时，与已经患有哮喘的儿童相比。潜在的应用和好处：这个项目将使我们能够弄清楚，靶向和阻断这些非常新的分子的作用，是否可能是阻止幼儿肺部早期损伤和瘢痕形成的最好方法，这些损伤和瘢痕形成发生在喘息和发展为哮喘的幼儿的肺部。

Context of the Research: Although approximately 40% of children under 5 years old wheeze, most grow out of their symptoms, and only some of the wheezers, (about one-third) develop asthma by school-age. We know that children who develop asthma have damage and scarring of the tubes (airways) in their lungs very early, between about 1 and 3 years of age, which remains at least until early adulthood. The factors that determine which preschool wheezers will develop asthma include a genetic susceptibility, development of early allergies and also getting early lung infections, especially with viruses. We are not able to predict which preschool wheezers will develop asthma, and importantly, there are no medicines which stop children from having reduced lung function and lessen airway scarring and damage. It is difficult to make measurements of lung scarring in very young children, since this needs samples taken from the lungs during a general anaesthetic. We have already developed a novel newborn mouse model to mimic how early preschool wheeze in infants caused by allergies leads to school-aged asthma. We have used house dust mites to cause mouse asthma. So far, we have shown that two chemicals seem very important in causing this type of allergic asthma. They are called interleukin (IL)-33 and activin. We think that these are new molecules whose action could be blocked as a treatment to stop the development of asthma from preschool wheeze. However, we have not yet explored the effect of virus infection in this model, and critically, as happens to young children, we have not looked at the interplay of viruses and allergies in our mouse model. Aims and Objectives: The aim of this project is therefore to make a newborn mouse model of virus lung infection, using 2 viruses that cause wheezing in young children. We will then look at the production of the important molecules that we have already found in the allergic asthma model in the virus infection model alone, and when both virus infection and house dust mites are used together. We think that the molecules will have different importance in young mice which are still developing disease compared to older mice with the full blown disease. Once we have established the important molecules that are involved in virus induced disease, allergy induced disease, and a combination of both, we will confirm the findings from the animal experiments in samples from children with severe symptoms. At the Brompton Hospital, we have developed a programme of using a special camera (bronchoscope) to look into the lungs of children with really severe wheeze or asthma to help to work out why their symptoms are so bad. In addition, if the child's parents agree, we have permission from the ethics committee to use any excess samples that remain after the clinical report for research. We will look at blood samples, airway washings and tiny pieces of tissue (biopsies) from the airways, and compare preschool children who only wheeze with virus infections, to those who wheeze with and without viruses, to school-aged children who have asthma. The samples are so tiny that we need to make targeted measurements, hence the need for the animal model to guide us as to which molecules are most promising. We will ascertain the role of at least 2 new molecules (IL-33 and activin) in the development of asthma from preschool wheeze. By also comparing the molecules in preschool children with wheezing to those in older children with asthma, we will be able to decide whether blocking one or other of the molecules may be better for treating younger children, when they are developing asthma, compared to older children who already have asthma. Potential Applications and Benefits: This project will allow us to work out whether targeting and blocking the action of these very new molecules might be the best way of stopping the very early damage and scarring that occurs in the lungs of young children that wheeze and develop asthma.