Functional and structural relationships of the peripheral airways in chronic asthma

现在认为，气道壁增厚（气道重塑），哮喘患者持续气道炎症的结果，显着有助于哮喘的症状和死亡风险。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。一些重要的问题仍有待阐明：什么是组织的变化，重塑的确切顺序？在没有过敏原刺激的情况下，哪些重塑成分是可逆的？什么时候气道重塑不可逆转？抗炎药物的早期干预在减少长期重塑方面是否有长期益处？由于很少有合适的模型来解决这些类型的重塑问题，我们建议利用一个大型的慢性哮喘动物模型来解决这些问题。该建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。考虑到绵羊气道的结构、生理学和哮喘病理生理学与人类气道相似，绵羊模型非常适合实现这些目标。新的实验设计是暴露个体绵羊中四个空间上分离的肺区域（段），每周重复给予HDM的持续时间不同。该提案的优势在于，可以在一只绵羊中评估来自连续重建阶段的挑战段的肺功能和结构。另一项单独的实验将研究在暴露于HDM停止后连续数月内，长期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理解。这将增加改善目前治疗的机会，并允许设计新的策略来更有效地治疗哮喘。

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.