Functional and structural relationships of the peripheral airways in chronic asthma

目前认为，气道壁增厚(气道重塑)是哮喘患者持续气道炎症的结果，对哮喘的症状和死亡风险有显著影响。尽管该领域最近取得了进展，但仍有许多临床相关问题尚未得到解决。一些需要阐明的重要问题是：重塑过程中组织变化的确切顺序是什么？在没有过敏原刺激的情况下，哪些重构成分是可逆的？在什么情况下，呼吸道重塑变得不可逆转？在减少长期重塑方面，早期抗炎药物干预是否有长期益处？由于几乎没有合适的模型来解决这些类型的重塑问题，我们建议利用慢性哮喘的大型动物模型来解决这些问题。这项提议的主要重点之一是确定重塑不同阶段的生物标志物或功能指数。绵羊模型很好地实现了这些目标，因为绵羊呼吸道的结构、生理学和哮喘病理生理学与人类呼吸道相似。这一新颖的实验设计是在每周重复服用HDM的不同持续时间内，暴露出绵羊四个空间上分离的肺区(段)。该方案的优点在于，可以在一只绵羊身上评估连续重塑阶段的肺功能和结构。另一项单独的实验将检查在停止接触HDM后的连续几个月里，长期接受HDM治疗的肺段的肺结构和功能如何恢复正常。预计从这项研究中获得的信息将导致对慢性哮喘疾病机制的更基本的了解。这将增加改进目前治疗方法的机会，并允许制定更有效地治疗哮喘的新策略。

It is now considered that airway wall thickening (airway remodeling), a consequence of persistent airway inflammation in asthmatics, significantly contributes to the symptoms and risk of death from asthma. Despite recent advances in the field, there are still many clinically relevant questions that have not been addressed. Some important issues still to be elucidated are: What is the precise sequence of tissue changes in remodeling? Which components of remodeling are reversible in the absence of allergen provocation? At what point does airway remodeling become irreversible? Does early intervention with anti-inflammatory medication have long term benefits in terms of reducing long-term remodeling? As there have been few appropriate models for addressing these types of remodeling issues, we propose to utilise a large animal model for chronic asthma to address these questions. One of the main focuses of this proposal is to identify biomarkers or functional indices of the different stages of remodelling. The sheep model is well placed to achieve these objectives given that the structure, physiology and asthma pathophysiology of sheep airways is similar to human airways. The novel experimental design is to expose four spatially separate lung regions (segments) in individual sheep with different durations of repeated weekly doses of HDM. The strength of the proposal is that lung function and structure of challenged segments from successive stages of remodeling can be assessed in one sheep. A separate experiment will examine how lung structure and function return to normal in chronically HDM-treated lung segments over successive months after exposure to HDM ceases. It is expected that information gained from this research will lead to a greater fundamental understanding of disease mechanisms in chronic asthma. This will increase the chances of improving current treatments, and allows for new strategies to be devised for treating asthma more effectively.