Investigating the Role of ADAM8 in Allergic Airway Inflammation

研究 ADAM8 在过敏性气道炎症中的作用

• 批准号: 7613171
• 负责人: Martin Daniel Knolle
• 金额: $ 5.53万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-30 至 2010-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613171
• 关键词: Adverse effects; Affect; American; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Asthma; Backcrossings; Binding; Biology; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Adhesion; Cell surface; Data; Disease; Disintegrin Domain; Disintegrins; Family; Genes; Genetic; Goals; Goblet Cells; Growth Factor; Heterogeneity; In Vitro; Inbred BALB C Mice; Incidence; Inflammation Mediators; Inflammatory; Integrins; Irrigation; Lead; Ligands; Lung; MMP2 gene; MMP8 gene; Metalloproteases; Metaplasia; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Ovalbumin; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Process; Public Health; Research; Role; Sampling; Surface; Testing; Variant; Wild Type Mouse; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; chemokine; cytokine; eosinophil; granulocyte; improved; macrophage; methacholine; migration; monocyte; mortality; novel; receptor

DESCRIPTION (provided by applicant): Little is currently known about anti-inflammatory pathways in asthma. Our novel studies have identified potent anti-inflammatory activities for ADAMS in allergic airway inflammation (AAI) in mice. The goal of this project is investigate the mechanisms by which ADAMS limits AAI and AHR in mice. In the long term, this research may lead to novel treatments for patients with asthma. ADAMs are transmembrane proteinases with a disintegrin and a metalloproteinase domain. ADAMs have the potential to regulate inflammatory processes in the lung because they shed and thereby regulate the biologic activites of cytokines, growth factors, and apoptosis ligands, and receptors for these molecules from cell surfaces. ADAMs also bind to integrins to regulate cell adhesion and migration. Little is known about the roles of ADAMs in asthma. Our preliminary studies show that ADAMS-/- mice with AAI have increased airway macrophage accumulation and increased airway hyper-responsiveness (AHR) to methacholine challenges compared to WT mice with AAI. This indicates that ADAMS has an anti-inflammatory role in AAI. We will investigate the mechanisms involved by pursuing the following Specific Aims: Specific Aim 1: Test the hypothesis that ADAMS reduces AAI and AHR in the pure BALB/c murine strain and fully characterize the phenotype of ADAMS-/- mice in this strain. We will compare the following in ovalbumin- or PBS-treated BALB/c ADAMS-/- versus BALB/c WT littermate control mice: 1) AAI in bronchoalveolar lavage (BAL) samples and lung sections; Th1, Th2, and anti-inflammatory cytokines in BAL fluid samples; and airway goblet cell metaplasia; and 2) AHR to methacholine challenges using FlexiventTM analysis. Specific Aim 2: We will test the hypothesisthat ADAMS reduces macrophage accumulation in the lungs of BALB/c mice with AAI by: 1) increasing apoptosis of airway macrophages during AAI; and/or 2) reducing monocyte transendothelial migration during AAI; and/or 3) proteolytically inactivating monocyte chemokines in the lung during AAI. Specific Aim 3: We will test the hypothesis that ADAMS limits AHR in BALB/c mice with AAI by reducing macrophage accumulation in murine airways. We will test whether depleting macrophages in ADAM8-/- mice with AAI reduces AHR to methacholine challenges in these mice. Relevance to public health: Asthma is a common disease which affected 15.7 million Americans in 2005. Current therapies are sometimes ineffective or have undesirable side-effects. Thus, there is a great need to new and improved treatments to the high limit morbidity and mortality associated with asthma.

描述（由申请人提供）：目前对哮喘的抗炎途径知之甚少。我们的新研究已经确定了亚当斯在小鼠过敏性气道炎症（AAI）中的有效抗炎活性。本项目的目的是研究亚当斯限制小鼠AAI和AHR的机制。从长远来看，这项研究可能会为哮喘患者带来新的治疗方法。亚当斯是具有去整合素和金属蛋白酶结构域的跨膜蛋白酶。亚当斯具有调节肺中的炎症过程的潜力，因为它们从细胞表面脱落并从而调节细胞因子、生长因子和凋亡配体以及这些分子的受体的生物活性。亚当斯还与整联蛋白结合以调节细胞粘附和迁移。关于亚当斯在哮喘中的作用知之甚少。我们的初步研究表明，与AAI WT小鼠相比，AAI亚当斯-/-小鼠气道巨噬细胞积聚增加，气道高反应性（AHR）增加乙酰甲胆碱的挑战。这表明亚当斯在AAI中具有抗炎作用。我们将通过追求以下具体目标来研究所涉及的机制：具体目标1：检验亚当斯降低纯BALB/c小鼠品系中AAI和AHR的假设，并充分表征该品系中亚当斯-/-小鼠的表型。我们将比较卵清蛋白或PBS处理的BALB/c亚当斯-/-与BALB/c WT同窝对照小鼠的以下结果：1）支气管肺泡灌洗（BAL）样本和肺切片中的AAI; BAL液样本中的Th 1、Th 2和抗炎细胞因子;以及气道杯状细胞化生;以及2）使用AnchaventTM分析的乙酰甲胆碱激发的AHR。具体目标二：我们将测试以下假设：亚当斯通过以下方式减少AAI BALB/c小鼠肺中的巨噬细胞蓄积：1）AAI期间增加气道巨噬细胞的凋亡;和/或2）AAI期间减少单核细胞跨内皮迁移;和/或3）AAI期间蛋白水解灭活肺中的单核细胞趋化因子。具体目标3：我们将检验以下假设：亚当斯通过减少小鼠气道中的巨噬细胞积聚来限制AAI BALB/c小鼠中的AHR。我们将测试用AAI消耗ADAM 8-/-小鼠中的巨噬细胞是否会降低这些小鼠中乙酰甲胆碱攻击的AHR。与公共卫生的相关性：哮喘是一种常见疾病，2005年影响了1570万美国人。目前的疗法有时是无效的或具有不期望的副作用。因此，非常需要新的和改进的治疗方法来限制与哮喘相关的高发病率和死亡率。