Novel role for CD163 in ozone induced alterations of pulmonary immunity

CD163 在臭氧诱导的肺免疫改变中的新作用

基本信息

批准号：
9762914
负责人：
Kymberly Mae Gowdy
金额：
$ 51.67万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762914
关键词：
Acute Acute Lung Injury Affect Air Pollutants Air Pollution Alveolar Macrophages Anti-inflammatory Apoptotic Area Bacterial Translocation Biological Biological Assay Biological Markers Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Bronchoscopy Cell surface Cells Chronic Clear Cell Cleaved cell Complex Data Development Emergency Situation Environmental Pollutants Epidemiology Exposure to Family Frequencies Health Heme Hemoglobin Hemoglobin concentration result Hospitalization Host Defense Hour Human Immunity Impairment Incidence Infection Inflammation Inflammatory Inflammatory Response Injury Klebsiella pneumonia bacterium Knowledge Laboratories Link Lung Lung Inflammation Lung diseases Lung infections Mediating Mediator of activation protein Membrane Molecular Mus Neutrophilia Organ Oxides Ozone Pathway interactions Phagocytosis Pneumococcal Infections Population Predisposition Public Health Pulmonary Inflammation Research Resolution Respiratory Tract Infections Role SR-B proteins Sampling Schools Therapeutic Therapeutic Effect Translating United States Visit air filter base epidemiology study haptoglobin-hemoglobin complex heme oxygenase-1 human data human subject improved in vivo lung injury macrophage monocyte mouse model neutrophil novel ozone exposure pathogen pollutant receptor respiratory response scavenger receptor therapeutic evaluation

项目摘要

Ozone (O3) causes lung injury, exacerbates chronic pulmonary diseases, and increases susceptibility to respiratory infections. Epidemiological studies strongly associate air pollution exposures and incidence of respiratory infections, which is important since more than 1/3 of the United States population lives in areas exceeding the current O3 regulatory standards. Though O3 exposure clearly impairs pulmonary host defense, the specific molecular mechanisms enhancing respiratory pathogen susceptibility remain poorly understood. Defining these mechanisms requires linking molecular pathways modified by environmental pollutants to those critical to host- pathogen interactions. The scavenger receptor families are such a molecular pathway. In this proposal, we plan to study the scavenger receptor CD163 in O3-induced alterations of pulmonary immunity. CD163 is a class B scavenger receptor, expressed on monocytes and macrophages, which exists in both membrane-bound and soluble (sCD163) forms. Membrane CD163 clears cell-free hemoglobin (CFH) by recognizing and internalizing hemoglobin-haptoglobin complexes. Once recognized by CD163, the complex is degraded by heme-oxygenase-1 into anti-inflammatory byproducts. Delayed CFH clearance augments inflammatory responses, exacerbates lung diseases, and modifies macrophage phagocytosis and apoptotic cell clearance (efferocytosis) resulting in persistent inflammation and defective pathogen clearance. Defining the role of CD163 in O3-mediated macrophage functions could uncover a novel mechanism mediating O3-induced adverse health effects. Our preliminary studies indicate that CD163 expression is upregulated in bronchoalveolar lavage (BAL) macrophages from human subjects undergoing acute laboratory O3 exposure. Supporting the human data, mice exposed to O3 have increased BAL macrophage CD163 expression and BALF CFH. O3-exposed CD163 deficient mice demonstrate increased lung injury, neutrophilia and frequency of airspace apoptotic neutrophils. On the basis of these observations, we hypothesize that macrophage-dependent clearance of CFH is mediated by CD163, a mechanism that limits acute lung injury after O3, and maintains effective efferocytosis and pathogen phagocytosis. The studies proposed will define: 1) how CD163 limits pulmonary inflammation by promoting efferocytosis; and 2) how CD163 clearance of CFH maintains macrophage phagocytosis of pathogens. These studies are translational; integrating murine and human samples/observations. Completion of these studies would define a novel molecular pathway for O3-induced health effects and define a specific mechanism by which ambient pollutants mediate critical macrophage functions. Furthermore, studies with sCD163 could identify a therapeutic to mitigate O3-induced susceptibility to pulmonary infections.

臭氧（O3）引起肺损伤，加剧慢性肺部疾病，并增加呼吸道易感性感染。流行病学研究强烈关联空气污染的暴露和呼吸的发病率感染，这很重要，因为超过1/3的美国人口生活在超过该地区当前的O3监管标准。尽管O3暴露显然会损害肺部宿主防御增强呼吸道病原体易感性的分子机制仍然鲜为人知。定义这些机制需要将环境污染物修饰的分子途径与宿主至关重要的分子途径联系起来病原体相互作用。清道夫受体家族是这样的分子途径。在此提案中，我们计划研究了在O3诱导的肺免疫改变中的寻宝受体CD163。 CD163是B类在膜结合和可溶性（SCD163）表格。膜CD163通过识别和内在化清除无细胞血红蛋白（CFH）血红蛋白 - 热蛋白复合物。一旦被CD163识别，该复合物被血红素 - 氧合酶-1降解变成抗炎副产品。延迟的CFH清除率增加了炎症反应，加剧了肺疾病，修饰巨噬细胞吞噬作用和凋亡细胞清除率（吞噬作用），导致持续的炎症和病原体清除率有缺陷。定义CD163在O3介导的巨噬细胞中的作用功能可能会发现介导O3诱导的不良健康影响的新型机制。我们的初步研究表明CD163表达在人类受试者的支气管肺泡灌洗（BAL）巨噬细胞中上调接受急性实验室O3暴露。支持人类数据，暴露于O3的小鼠增加了BAL 巨噬细胞CD163表达和BALF CFH。 O3暴露的CD163缺乏小鼠表现出肺增加损伤，中性粒细胞和空域凋亡中性粒细胞的频率。根据这些观察，我们假设CFH的巨噬细胞依赖性清除率是由CD163介导的，CD163是限制的机制 O3后急性肺损伤，并保持有效的肿瘤病和病原体吞噬作用。研究提出的将定义：1）CD163如何通过促进肿瘤病来限制肺部炎症； 2）CD163如何 CFH的清除维持病原体的巨噬细胞吞噬作用。这些研究是翻译的。整合鼠和人类样品/观察。这些研究的完成将定义一种新颖的分子途径 O3引起的健康效应并定义了一种特定机制，环境污染物介导关键巨噬细胞功能。此外，对SCD163的研究可以鉴定出一种治疗方法来减轻O3诱导的对肺部感染的敏感性。