Development of an animal model of severe neutrophilic asthma

项目总结 这项提议的目标是建立一种类固醇抗中性粒细胞哮喘的动物模型，即 复制患者的症状，以了解潜在的细胞和分子病理。哮喘是一种 慢性炎症性疾病的特征是炎症细胞聚集，支气管高反应性， 粘液的产生，以及气道重塑和狭窄。根据疾病控制和预防中心的数据 预防，8.3%的美国人口(儿童和成人)患有不同程度的哮喘 严肃性。通常认为，呼吸道炎症是由Th2免疫反应引起的， 或嗜酸性粒细胞增多，这是哮喘发病机制的一个标志。然而，多份临床报告显示 高达50%的症状性哮喘患者痰中中性粒细胞计数升高。这个非- 嗜酸性哮喘通常对治疗哮喘的主要药物皮质类固醇类药物无效，而且 与支气管组织和痰中Th17细胞因子的存在有关。慢性阻塞性肺疾病的临床表现 中性粒细胞哮喘不同于嗜酸性哮喘，有证据表明上呼吸道反应异常。 目前，中性粒细胞哮喘的分子病理机制还知之甚少，主要是由于 缺乏合适的动物模型。由于其高得惊人的流行率，迫切需要 了解中性粒细胞哮喘的病理生理学，指导靶向治疗。来自不同来源的T细胞 个体表现出不同的分化为不同的效应器谱系的倾向，这突出了他们的 易患过敏性和炎症性疾病。关于人类受试者的全基因组关联研究 提供了关于控制T细胞反应的内在因素的有价值的信息，但这些结果是高度 受各种环境因素的影响，包括天气和饮食。将环境影响降至最低 因素，我们检测了从杂交鼠多样性小组分离的T细胞中细胞因子的表达，该小组由 107个普通自交系和重组自交系品系，饲喂相同的日粮，饲养在特定的 无病原体条件。这些努力的结果是鉴定出了都显示出强大的Th2的小鼠品系 反应，但有不同程度的Th17反应。根据我们的发现，我们的具体目标是1) 利用T细胞高表达的小鼠品系建立新的中性粒细胞哮喘动物模型 Th2和Th17的分化倾向和2)决定细胞和分子机制 这些小鼠患中性粒细胞哮喘的潜在倾向。

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.