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

学龄前喘息和哮喘发生和传播的分子机制：白细胞介素 (IL)-33 和激活素 A 的作用

• 批准号: MR/J010529/1
• 负责人: Sejal Saglani
• 金额: $ 20.43万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ010529%2F1
• 关键词: Molecular; mechanisms; underlying; development; propagation

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.

研究背景：虽然大约40%的5岁以下儿童会发生喘息，但大多数人长大后症状消失，只有一些喘息者（约三分之一）在学龄前发展为哮喘。我们知道，患有哮喘的儿童在很小的时候（大约1到3岁之间）就会出现肺部管道（气道）损伤和疤痕，这种情况至少会持续到成年早期。决定哪些学龄前喘息者会患上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，特别是病毒感染。我们无法预测哪些学龄前喘息者会发展为哮喘，重要的是，没有药物可以阻止儿童肺功能下降，减轻气道瘢痕和损伤。很难对非常年幼的儿童进行肺瘢痕测量，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，以模拟过敏引起的婴幼儿早期喘息如何导致学龄期哮喘。我们用室内尘螨来引起小鼠哮喘。到目前为止，我们已经表明，两种化学物质似乎在引起这种类型的过敏性哮喘中非常重要。它们被称为白细胞介素（IL）-33和activin。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，以阻止哮喘从学龄前喘息的发展。然而，我们还没有探索病毒感染在这个模型中的影响，而且关键的是，正如发生在幼儿身上的那样，我们还没有研究病毒和过敏在我们的小鼠模型中的相互作用。宗旨和目标：因此，本项目的目的是使用两种引起幼儿喘息的病毒，制作病毒性肺部感染的新生小鼠模型。然后，我们将研究我们已经在过敏性哮喘模型中发现的重要分子的产生，无论是在单独的病毒感染模型中，还是在同时使用病毒感染和屋尘螨时。我们认为，这些分子在仍在发展疾病的年轻小鼠和患有完全疾病的老年小鼠中具有不同的重要性。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结合有关的重要分子，我们将在患有严重症状的儿童样本中证实动物实验的结果。在布朗普顿医院，我们开发了一个项目，使用一种特殊的摄像机（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任何多余样本进行研究。我们将观察血液样本、气道冲洗液和气道的微小组织（活检），并将仅因病毒感染而喘息的学龄前儿童与有病毒和无病毒喘息的学龄前儿童以及患有哮喘的学龄儿童进行比较。这些样品非常小，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。我们将确定至少两种新分子（IL-33和激活素）在学龄前喘息性哮喘发展中的作用。通过比较学龄前喘息儿童与年龄较大的哮喘儿童的分子，我们将能够决定是否阻断一种或另一种分子可能更好地治疗年龄较小的儿童，当他们发展为哮喘时，与年龄较大的儿童相比，已经患有哮喘。潜在的应用和益处：该项目将使我们能够确定靶向和阻断这些非常新的分子的作用是否可能是阻止发生在喘息和发展哮喘的幼儿肺部的早期损伤和瘢痕形成的最佳方法。

项目成果

Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33.

• DOI: 10.1016/j.jaci.2015.01.016
• 发表时间: 2015-08
• 期刊: The Journal of allergy and clinical immunology
• 作者: Castanhinha S;Sherburn R;Walker S;Gupta A;Bossley CJ;Buckley J;Ullmann N;Grychtol R;Campbell G;Maglione M;Koo S;Fleming L;Gregory L;Snelgrove RJ;Bush A;Lloyd CM;Saglani S
• 通讯作者: Saglani S

IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma.

• DOI: 10.1016/j.jaci.2013.04.012
• 发表时间: 2013-09
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Saglani, Sejal;Lui, Stephen;Ullmann, Nicola;Campbell, Gaynor A.;Sherburn, Rebekah T.;Mathie, Sara A.;Denney, Laura;Bossley, Cara J.;Oates, Timothy;Walker, Simone A.;Bush, Andrew;Lloyd, Clare M.
• 通讯作者: Lloyd, Clare M.