Effects of ozone exposure on expression and function of surfactant protein D

臭氧暴露对表面活性蛋白D表达和功能的影响

• 批准号: 7941812
• 负责人: ANGELA HACZKU
• 金额: $ 50万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941812
• 关键词: Air Pollutants; Air Pollution; Allergens; Antibodies; Appearance; Area; Asthma; Binding; Biological Assay; Biotin; Bone Marrow; Breathing; C-terminal; CCL17 gene; Carbohydrates; Cell Culture Techniques; Cell surface; Cells; Chronic; Chronic Obstructive Airway Disease; Collagen; Collagen Receptors; Complex; Dendritic Cells; Dependovirus; Disease; Distal; Environmental Exposure; Epithelial; Gene Expression; Genetic; Homeostasis; Human; Immune; Immune system; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Laboratories; Liquid substance; Lung; Lymphoid; Mediating; Mediator of activation protein; Medical; Mission; Modeling; Morbidity - disease rate; Mus; Myelogenous; N-terminal; NF-kappa B; National Institute of Environmental Health Sciences; Nitrogen; Outcome; Oxygen; Ozone; PTPNS1 gene; Pathology; Patients; Phagocytes; Phase; Post-Translational Protein Processing; Predisposition; Production; Property; Protective Agents; Public Health; Pulmonary Surfactant-Associated Protein D; Receptor Signaling; Regulation; Resolution; Role; Signal Transduction; Structure of parenchyma of lung; TNF gene; Testing; Therapeutic; Thymus Gland; Time; Translational Research; airway hyperresponsiveness; airway inflammation; allergic airway inflammation; asthmatic airway; autocrine; base; calreticulin; chemokine; cytokine; gel electrophoresis; gene replacement; in vivo; knockout gene; lung development; lung injury; lymph nodes; migration; mortality; mutant; novel strategies; oxidative damage; ozone exposure; prevent; public health relevance; receptor binding; response

DESCRIPTION (provided by applicant): This application is submitted in response to the broad challenge area of Translational Science (15-ES-101*) and the specific challenge topic of "Effects of environmental exposures on phenotypic outcomes using non- human models." Chronic inflammatory diseases of the airways such as asthma or chronic obstructive pulmonary disease (COPD) arise from a complex interaction between genetic factors and environmental exposures. Our laboratory has established murine models that mimic the pathology of ozone (O3)-induced exacerbation of airway inflammation. The current application will utilize this model together with gene knockout and conditional over expressor mice to investigate the importance in changes in gene expression and post translational modifications of surfactant protein D, an immunoprotective component of the proximal and distal airway lining. Our studies showed that inhalation of O3, a common air pollutant, induced a significant exacerbation of the asthmatic changes in allergen sensitized mice together with the appearance of abnormal, trimeric SP-D and activated, myeloid dendritic cells. We hypothesize that SP-D acts as a "master switch" between the onset and resolution of airway inflammation: Native SP-D is a suppressor of activation of the proinflammatory dendritic cells and acts through the C-terminal by binding to the negative signal receptor SIRP. In contrast, a de-oligomerized (trimeric) SP-D that has undergone oxidative damage by O3, activates dendritic cells through the exposed N-terminal by ligating the collagen receptor, calreticulin/CD91. The asthmatic airways are particularly susceptible to O3-induced changes in the SP-D molecule because of the presence of mature myeloid dendritic cells carrying the calreticulin/CD91. Aim 1 is to investigate the hypothesis that O3-induced exacerbation of allergic airway inflammation is associated with the appearance of SP-D trimers with an active N-terminal domain. Aim 2 is to study the hypothesis that native SP-D binds to SIRP? and delivers inhibitory signals while trimeric SP-D binds to calreticulin/CD91 and induces proinflammatory activation of NF-kB, TNF and TARC (Ccl17) release by dendritic cells. Aim 3 is to investigate whether the C- terminal suppresses and the trimeric SP-D activates epithelial migration of bone marrow derived, proinflammatory dendritic cells. In vitro bone-marrow derived dendritic cell cultures and in vivo conditional SP-D expressing mice and adeno-associated virus gene replacement of wild-type and mutant SP-D (mimicking either the C-terminal of the molecule or the SP-D trimer) will be studied for maturation and migration of dendritic cells. Results of this project will yield clinically and scientifically significant information on the role of SP-D in regulation of the innate immune system during O3-induced airway changes and on potential therapeutic utilization of this naturally occurring immuno-protective agent in the lung. PUBLIC HEALTH RELEVANCE: Air pollution, particularly O3, induces exacerbations of asthma that substantially worsen morbidity and mortality. In healthy individuals inhalation of O3 elicits mechanisms such as homeostatic increase in SP-D synthesis that protect the lung from development of chronic damage. Currently neither the mechanism of O3-induced SP-D production nor the consequent alterations of the pulmonary immune system is understood. Results from this application will define the implications of SP-D in O3-induced exacerbation of asthma and will provide novel approaches to manipulate the pulmonary immune system.

描述（由申请人提供）：该申请是针对转化科学的广泛挑战领域（15-ES-101*）提交的，以及“环境暴露对使用非人类模型的表型结果的影响”的具体挑战主题。 气道的慢性炎症性疾病，例如哮喘或慢性阻塞性肺疾病（COPD）是由于遗传因素与环境暴露之间的复杂相互作用引起的。我们的实验室建立了模仿臭氧病理（O3）引起的气道炎症病理的鼠模型。当前的应用将利用该模型以及基因敲除和有条件在表达小鼠上的条件来研究基因表达变化的重要性，并在表面活性剂蛋白D的翻译后修饰（近端和远端气道衬里的免疫保护成分）的翻译修饰。 我们的研究表明，一种常见的空气污染物O3吸入会引起过敏原敏化小鼠哮喘变化的显着加重，以及异常，三聚体SP-D和激活的髓样树突状细胞的出现。我们假设SP-D充当气道炎症的发作和分辨率之间的“主开关”：天然SP-D是促炎树突状细胞激活的抑制剂，并通过与阴性信号受体SIRP结合通过C末端起作用。相比之下，通过将胶原蛋白受体Calreticulin/cd91绑扎的N端，通过O3受到O3的氧化损伤的去脱聚（三聚体）SP-D激活树突状细胞。 哮喘气道特别容易受到O3诱导的SP-D分子变化的影响，因为存在带有钙网蛋白/CD91的成熟髓样树突状细胞。目的1是研究以下假设：O3诱导的过敏性气道炎症加重与具有活性N末端结构域的SP-D夹子的出现有关。 AIM 2是研究天然SP-D与SIRP结合的假设？ 并提供抑制性信号，而三聚体SP-D与钙网蛋白/CD91结合，并诱导NF-KB，TNF和TARC（CCL17）释放的树突状细胞释放NF-KB，TNF和TARC（CCL17）。 AIM 3是研究C-末端抑制和三聚体SP-D是否激活了衍生的，促炎的树突状细胞的上皮迁移。体外骨髓衍生的树突状细胞培养和体内有条件的SP-D表达小鼠以及与野生型和突变体SP-D的替代腺相关病毒基因替代（模拟分子的C端或SP-D Trimer的C末端），以进行树突状细胞的成熟和迁移。该项目的结果将在O3诱导的气道变化过程中，以及在肺中这种自然存在的免疫保护剂的潜在治疗利用过程中，在临床和科学上有重要的信息。 公共卫生相关性：空气污染，尤其是O3，引起哮喘的加剧，这显着恶化了发病率和死亡率。 在健康的个体中，对O3的吸入引起了SP-D合成的稳态增加，从而保护肺部免受慢性损害的发展。目前，尚未了解O3诱导的SP-D产生的机制，也没有理解肺免疫系统的变化。该应用的结果将定义SP-D在O3诱导的哮喘加重中的含义，并将提供操纵肺免疫系统的新方法。