Airway Biology of Acute Asthma: Translational Studies

描述（由申请人提供）： 哮喘的特征在于慢性IgE依赖性气道炎症、气道反应性增加和疾病的周期性恶化。吸入过敏原（一种IgE介导的获得性免疫刺激）、LPS和O3（先天性刺激）可诱导哮喘急性加重，伴嗜酸性粒细胞增加、气道反应性和肺功能下降。我们已经观察到O3和LPS增强了对变应原的反应，变应原激发似乎改变了对O3和LPS的反应，这表明先天免疫和获得性免疫之间的相互作用介导了哮喘恶化。在哮喘急性发作模型的开发中，我们重点关注炎症、肺量测定和气道反应性（基于肺量测定终点）。然而，哮喘急性发作还涉及粘液分泌、粘液堵塞和粘液纤毛清除（MCC）受损。我们的小组已经开发了MCC评估技术，我们渴望将这一措施纳入哮喘急性发作的研究，以提高炎症刺激，炎症细胞和人体气道功能之间的关系的理解。我们将检验以下假设：获得性IgE诱导的炎症改变对先天性刺激的反应，先天性炎症增强抗原呈递和IgE反应元件，以及CD 11b（我们发现其与肺功能变化以及粒细胞流入非常相关）预测急性加重的严重程度（由炎症、反应性和MCC定义）。 我们将追求以下具体目标：SA 1：我们将检验已知上调气道巨噬细胞上共刺激分子的内毒素剂量将增强IgE介导的对吸入过敏原的反应的假设; SA 2：我们将检验先天免疫刺激物O3增加IgE介导的哮喘急性发作风险的假设，并确定潜在的干预靶点; SA 3：通过比较抗IgE抗体（奥马珠单抗）和安慰剂治疗的特应性哮喘患者对O3激发的反应，检验IgE调节O3介导的哮喘急性发作的假设。

DESCRIPTION (provided by applicant): Asthma is characterized by chronic IgE dependent airway inflammation, increased airway reactivity and periodic exacerbations of disease. Inhalation of allergen (an IgE mediated acquired immune stimulus), LPS and O3 (innate stimuli) can induce acute exacerbation of asthma, with increases in eosinophils, airway reactivity and decreased lung function. We have observed that O3 and LPS enhance response to allergen, and allergen challenge appears to modify response to O3 and LPS, suggesting interactions between innate and acquired immunity mediate asthma exacerbation. In development of our models of asthma exacerbation, we have focused on inflammation, spirometry and airway reactivity (which is based on spirometric endpoints). However, asthma exacerbation also involves mucus secretion, mucus plugging and impairment of mucociliary clearance (MCC). Our group has developed MCC assessment techniques and we are eager to incorporate this measure into studies of asthma exacerbation to improve understanding of the relationship between inflammatory stimuli, inflammatory cells and function of the human airway. We will test the hypotheses that acquired IgE induced inflammation modifies response to innate stimulation, that innate inflammation enhances antigen presentation and IgE response elements and that CD11b (which we have found correlates very well with changes in lung function as well as granulocyte influx) predicts severity of exacerbation as defined by inflammation, reactivity and MCC. We will pursue the following specific aims: SA1: We will test the hypothesis that doses of endotoxin known to upregulate co-stimulatory molecules on airway macrophages will enhance IgE mediated response to inhaled allergen; SA2: We will test the hypothesis that the innate immune stimulus O3 increases risk for IgE mediated asthma exacerbation and identify potential targets for intervention; SA3: To test the hypothesis that IgE modulates O3 mediated asthma exacerbation by comparing the responses of atopic asthmatics treated with anti-IgE (omalizumab) and placebo to O3 challenge.