Extracellular Matrix, Innate Immunity, and Ozone-induced Airways Disease

细胞外基质、先天免疫和臭氧诱发的气道疾病

• 批准号: 8652977
• 负责人: John W Hollingsworth
• 金额: $ 5.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652977
• 关键词: Adaptor Signaling Protein; Address; Affect; Air Pollutants; Alveolar Macrophages; Asthma; Binding; Biological; Biological Models; Bone Marrow; Breathing; Cardiovascular system; Cell membrane; Cell surface; Cells; Chimera organism; DNA Binding; Data; Development; Disease; Epithelium; Exposure to; Extracellular Matrix; Gene Targeting; Genes; Glycosaminoglycans; Health; Hospitalization; Human; Hyaluronan; Immune; Immune response; Knockout Mice; Lead; Ligands; Lung; Macrophage Activation; Mediating; Methodology; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nature; Oxidants; Ozone; Patients; Physiological; Play; Population; Role; Signal Transduction; System; Testing; Tissues; Toxin; Work; airway epithelium; airway hyperresponsiveness; cell type; in vivo; innovation; insight; interest; lung injury; macrophage; methacholine; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; osteopontin; oxidant stress; ozone exposure; reconstitution; respiratory; response; toll-like receptor 4; trafficking

DESCRIPTION (provided by applicant): Ambient ozone is associated with increased hospitalizations, respiratory illness, and increased cardiovascular mortality. Given the continuous exposure of the lung to a variety of airborne toxins, understanding the biologic mechanisms that regulate the patho-physiologic responses to common ambient air pollutants is of considerable interest to human health. In previous work, we have demonstrated a critical role for the innate immune gene, toll-like receptor 4, in the development of airway hyperresponsiveness after exposure to ozone. We now recognize that degradation products of the extracellular matrix glycosaminoglycan hyaluronan (HA) accumulate following ozone exposure. Fragments of this glycosaminoglycan can function as an endogenous ligand of tlr4 activating of innate immune responses. Our data support that HA fragments regulate the airway physiological response to ozone. The instillation of HA fragments into the lungs of mice leads to tlr4-dependent airway hyperresponsiveness. In addition, we now provide data that the development of HA-dependent airway hyperresponsiveness requires the downstream adaptor molecule MyD88. However, the cell-types and specific mechanisms, which regulate the physiologic response to matrix fragments in the lung, remain unexplored. We provide novel evidence that osteopontin contributes to the biological response to ozone and our data suggest that osteopontin can function as an adaptor molecule during innate immune response to oxidant lung injury. Clear understanding of the mechanisms, which regulate the development of airway hyperresponsiveness after exposure to ambient ozone, could provide a novel therapeutic approach to many forms of airways disease including asthma. Furthermore, we provide evidence that NF-?B is activated in lung macrophages and airway epithelia following either ozone exposure or HA challenge. Collectively, our data suggest that matrix fragments accumulate in the context of non-infectious air pollutant exposure and that macrophage-derived innate immunity play a central role in mediating airway hyperreactivity. These data have led us to test the hypothesis that exposure to ambient ozone generates hyaluronan degradation products which mediate airway hyperresponsiveness through activation of macrophage-derived NF-?B in a manner dependent on the adaptor proteins MyD88 and OPN. We will address this hypothesis through the following specific aims. Specific Aim 1: Define the roles of MyD88 and NF-?B activation in macrophages and airway epithelia for the complete biologic response to ozone, and to hyaluronan fragments. Specific Aim 2: Define the role of intracellular OPN in response to ozone inhalation and recruitment of MyD88 to the cell surface of macrophages. Specific Aim 3: Utilizing human BALF define the role of soluble hyaluronan in MyD88, and OPN- dependent airway hyperresponsiveness to methacholine and NF-?B activation.

描述（由申请人提供）：环境臭氧与住院增加，呼吸道疾病和心血管死亡率增加有关。鉴于肺部不断暴露于各种空气中毒素，因此了解调节对普通环境空气污染物的病理生理反应的生物学机制对人类健康具有相当大的兴趣。在以前的工作中，我们在暴露于臭氧后的气道高反应性发展中表现出了先天免疫基因Toll样受体4的关键作用。现在，我们认识到细胞外基质糖胺聚糖透明质酸（HA）的降解产物会在臭氧暴露后积累。该糖胺聚糖的片段可以作为TLR4先天免疫反应激活的内源性配体。我们的数据支持碎片调节气道生理反应对臭氧的反应。将HA碎片滴入小鼠的肺部导致TLR4依赖性气道高反应性。此外，我们现在提供数据，表明HA依赖性气道高反应性的发展需要下游适配器分子MyD88。但是，调节对肺中基质片段的生理反应的细胞类型和特定机制仍未得到探索。我们提供了新的证据，表明骨桥蛋白有助于对臭氧的生物学反应，我们的数据表明，骨桥蛋白在对氧化剂肺损伤的先天免疫反应期间可以用作衔接蛋白。对这种机制的清晰了解，这些机制调节了暴露于环境臭氧后气道高反应性的发展，可以为包括哮喘在内的多种形式的气道疾病提供一种新型的治疗方法。此外，我们提供的证据表明，在臭氧暴露或HA挑战之后，NF-？B在肺巨噬细胞和气道上皮中被激活。总的来说，我们的数据表明，基质片段在非感染空气污染物暴露的背景下积累，并且巨噬细胞衍生的先天免疫在介导气道高反应性中起着核心作用。这些数据导致我们检验了以下假设：暴露于环境臭氧会产生透明质酸降解产物，从而通过巨噬细胞衍生的NF-？b以依赖于衔接子蛋白myd88和opn的方式激活巨噬细胞的NF-？b，从而介导气道高反应。我们将通过以下特定目标解决这一假设。具体目标1：定义MyD88和NF-？B激活在巨噬细胞和气道上皮中的作用，以使其对臭氧的完整生物反应以及对透明质酸片段的完整生物反应。具体目标2：定义细胞内OPN对臭氧吸入和将MyD88募集到巨噬细胞表面的作用。特定目标3：利用人BALF定义了MyD88中可溶性透明质酸的作用，以及对甲基苯胺和NF-？B激活的OPN依赖性气道高反应性。