Novel role for CD163 in ozone induced alterations of pulmonary immunity

臭氧会导致肺损伤，加重慢性肺部疾病，并增加对呼吸道的易感性。 感染。流行病学研究强烈地将空气污染暴露与呼吸道疾病的发病率联系在一起。 感染，这一点很重要，因为超过三分之一的美国人口生活在超过 目前的臭氧监管标准。尽管臭氧暴露明显损害了肺宿主防御，但特异性 增加呼吸道病原体敏感性的分子机制仍然知之甚少。定义这些 机制需要将环境污染物修饰的分子途径与对宿主至关重要的分子途径联系起来。 病原体相互作用。清道夫受体家族就是这样一种分子途径。在这项提案中，我们计划 研究清道夫受体CD163在臭氧诱导的肺免疫改变中的作用。CD163为B级 清道夫受体，表达于单核细胞和巨噬细胞，存在于膜结合型和 可溶性(SCD163)形式。膜CD163通过识别和内化清除无细胞血红蛋白 血红蛋白-结合珠蛋白复合体。一旦被CD163识别，该复合体就会被血红素加氧酶-1降解 转化为抗炎副产品。CFH清除延迟会加剧炎症反应，加剧肺部 疾病，并改变巨噬细胞吞噬和凋亡细胞清除(泡沫化)，导致 持续的炎症和缺陷的病原体清除。确定CD163在臭氧介导的巨噬细胞中的作用 这些功能可能会揭示一种新的机制，介导臭氧引发的不良健康影响。我们的初步研究 人肺泡灌洗巨噬细胞CD163表达上调 正在经历实验室的急性臭氧暴露。支持人类数据的是，暴露在臭氧中的小鼠BAL增加 巨噬细胞CD163表达与BALF CFH臭氧暴露的CD163缺陷小鼠肺功能增加 损伤、中性粒细胞增多和空隙内中性粒细胞凋亡的频率。根据这些观察，我们 假设巨噬细胞依赖的CFH清除是由CD163介导的，CD163是一种限制CFH的机制 O3后急性肺损伤，并维持有效的吞噬作用和病原体吞噬作用。这些研究 提议将定义：1)CD163如何通过促进吞噬作用来限制肺部炎症；以及2)CD163如何 清除CFH可维持巨噬细胞对病原体的吞噬作用。这些研究是翻译的；整合的 小鼠和人类样本/观察。这些研究的完成将定义一种新的分子途径 臭氧诱导的健康影响，并定义环境污染物调节关键环境的特定机制 巨噬细胞的功能。此外，对sCD163的研究可以确定一种缓解臭氧诱导的治疗方法 对肺部感染易感性。

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.