Development of an animal model of severe neutrophilic asthma

项目摘要 本研究的目的是建立一种激素抵抗型嗜酸粒细胞性哮喘的动物模型， 复制患者症状，以了解潜在的细胞和分子病理学。哮喘是一 慢性炎性疾病的特征在于炎性细胞的募集，支气管高反应性， 粘液产生以及气道重塑和狭窄。根据疾病控制中心和 预防，8.3%的美国人口（儿童和成人）患有哮喘， 严重性。通常认为气道炎症是由Th 2免疫应答引起的， 或嗜酸性粒细胞增多，这是支气管哮喘发病机制的标志。然而，多份临床报告显示， 高达50%的有症状的哮喘患者痰中性粒细胞计数升高。这个非- 嗜酸性粒细胞性哮喘通常对皮质类固醇（哮喘治疗的主要药物）无效， 与支气管组织和痰中Th 17细胞因子的存在相关。临床模式 嗜酸性粒细胞性哮喘与嗜酸性粒细胞性哮喘不同，其上气道反应异常。 目前，对嗜中性粒细胞性哮喘的分子病理学了解甚少，主要是由于 缺乏合适的动物模型。由于其惊人的高流行率，迫切需要 了解嗜肺性哮喘的病理生理学，为靶向治疗提供信息。不同类型的T细胞 个体表现出不同的倾向，分化成不同的效应谱系，这强调了他们的 易患过敏性和炎症性疾病。人类受试者的全基因组关联研究 提供了关于控制T细胞应答的内在因素的有价值的信息，但这些结果是高度错误的。 受各种环境因素的影响，包括天气和饮食。尽量减少环境影响 因子，我们检查了T细胞中的细胞因子表达，T细胞分离自杂交小鼠多样性小组， 107个普通近交系和重组近交系用相同的饲料喂养，并在特定的环境下饲养， 无病原体的条件这些努力已经鉴定出全部显示强Th 2的小鼠品系 反应，但具有不同程度的Th 17反应。根据我们的调查结果，我们的具体目标是：1） 使用具有高T细胞的小鼠品系开发一种新的嗜肺性哮喘动物模型， Th 2和Th 17分化的倾向和2）确定细胞和分子机制 潜在的嗜酸性哮喘倾向。

PROJECT SUMMARY The goal of this proposal is to establish an animal model for steroid-resistant neutrophilic asthma, that replicates patient symptoms to understand the underlying cellular and molecular pathology. Asthma is a chronic inflammatory disease characterized by recruitment of inflammatory cells, bronchial hyperreactivity, mucus production, and airway remodeling and narrowing. According to Centers for Disease Control and Prevention, 8.3% of the US population (children and adults) suffers from asthma with varying degree of severity. It has commonly been considered that airway inflammation is caused by the Th2 immune response, or eosinophilia, which is a hallmark of bronchial asthma pathogenesis. However, multiple clinical reports show that as high as 50% patients with symptomatic asthma have elevated sputum neutrophil counts. This non- eosinophilic asthma is often refractory to corticosteroids, the mainstay of asthma treatment, and is strongly associated with the presence of Th17 cytokines in the bronchial tissues and sputum. The clinical pattern of neutrophilic asthma is different from eosinophilic asthma with evidence of abnormal upper airway responses. Currently, the molecular pathology underlying neutrophilic asthma is very poorly understood, mainly due to the lack of appropriate animal models. Due to its alarmingly high prevalence, there is an urgent need to understand the pathophysiology of neutrophilic asthma, to inform targeted therapy. T cells from diverse individuals show different propensity to differentiate into distinct effector lineages, which underscores their susceptibility to allergic and inflammatory diseases. Genome-wide association studies on human subjects provide valuable information about intrinsic factors governing T cell responses, but these results are highly influenced by various environmental factors including weather and diet. To minimize influence of environmental factors, we examined cytokine expressions in T cells isolated from a hybrid mouse diversity panel consisting of 107 common inbred and recombinant-inbred strains fed with the same diet and housed under specific pathogen-free conditions. These efforts have resulted in identification of mouse strains that all show strong Th2 responses, but have varying degree of Th17 responses. Based on our findings, our specific goals are to 1) develop a new animal model of neutrophilic asthma using the mouse strain with T cells that shows high propensity to both Th2 and Th17 differentiation and 2) determine the cellular and molecular mechanism underlying propensity to neutrophilic asthma in these mice.