Airway Biology of Acute Asthma: Translational Studies

描述(由申请人提供)： 哮喘的特征是慢性IgE依赖的呼吸道炎症，气道反应性增加和疾病的周期性加重。吸入过敏原(一种IgE介导的获得性免疫刺激)、内毒素和臭氧(天然刺激)可导致哮喘急性加重，嗜酸性粒细胞增加，呼吸道反应性增加，肺功能下降。我们观察到，臭氧和脂多糖增强了对变应原的反应，而变应原攻击似乎改变了对臭氧和脂多糖的反应，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的加重。在开发我们的哮喘恶化模型时，我们将重点放在炎症、肺活量测定和呼吸道反应性(基于肺活量测定终点)上。然而，哮喘加重也涉及粘液分泌、粘液堵塞和粘液纤毛清除障碍(MCC)。我们团队已经开发了MCC评估技术，我们渴望将这一方法纳入哮喘恶化的研究中，以提高对炎症刺激、炎症细胞和人类呼吸道功能之间关系的理解。我们将检验以下假设：获得性免疫球蛋白E诱导的炎症改变了对先天刺激的反应，先天炎症增强了抗原提呈和免疫球蛋白E反应元件，以及CD11b(我们发现它与肺功能的变化以及粒细胞内流非常相关)预测了炎症、反应性和MCC定义的恶化的严重程度。 我们将追求以下具体目标：SA1：我们将测试已知上调呼吸道巨噬细胞上共刺激分子的内毒素剂量将增强IgE介导的吸入性变应原反应的假设；SA2：我们将测试固有免疫刺激臭氧增加IgE介导的哮喘恶化风险的假设，并确定潜在的干预靶点；SA3：通过比较特应性哮喘患者接受抗IgE单抗(Omalizumab)和安慰剂治疗后对臭氧刺激的反应，测试IgE调节臭氧介导的哮喘加重的假设。

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.