Novel role for CD163 in ozone induced alterations of pulmonary immunity

臭氧（O3）会导致肺损伤，加重慢性肺部疾病，并增加对呼吸道疾病的易感性。 感染.流行病学研究将空气污染暴露与呼吸道感染发病率密切相关。 感染，这是重要的，因为超过1/3的美国人口生活在地区超过 目前的O3标准。虽然O3暴露明显损害肺宿主防御，但特异性 增强呼吸道病原体易感性的分子机制仍然知之甚少。定义这些 这些机制需要将环境污染物改变的分子途径与那些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的分子通路。在这份提案中，我们计划 研究清道夫受体CD 163在O3诱导的肺免疫改变中的作用。CD 163为B类 清道夫受体，在单核细胞和巨噬细胞上表达，存在于膜结合和 可溶性（sCD 163）形式。膜CD 163通过识别和内化清除无细胞血红蛋白（CFH） 血红蛋白-触珠蛋白复合物。一旦被CD 163识别，该复合物就被血红素加氧酶-1降解 转化为抗炎副产品延迟CFH清除增强炎症反应，加重肺 疾病，并改变巨噬细胞吞噬作用和凋亡细胞清除（巨噬细胞吞噬作用），导致 持续性炎症和病原体清除缺陷。确定CD 163在O3介导的巨噬细胞中的作用 功能可以揭示一种新的机制，介导O3引起的不良健康影响。我们的初步研究 表明在来自人受试者支气管肺泡灌洗（BAL）巨噬细胞中CD 163表达上调 实验室急性臭氧暴露支持人类数据，暴露于O3的小鼠的BAL增加 巨噬细胞CD 163表达和BALF CFH。O3暴露的CD 163缺陷小鼠显示肺 损伤、嗜中性粒细胞增多和空泡性凋亡中性粒细胞的频率。根据这些观察，我们 假设CFH巨噬细胞依赖性清除是由CD 163介导的，这是一种限制 急性肺损伤后O3，并保持有效的吞噬功能和病原体的吞噬。研究 提出将定义：1）CD 163如何通过促进红细胞增多来限制肺部炎症; 2）CD 163如何 CFH的清除维持了巨噬细胞对病原体的吞噬作用。这些研究是翻译的;整合的 鼠和人样本/观察结果。这些研究的完成将定义一种新的分子途径， O3引起的健康影响，并定义了一个特定的机制，环境污染物介导的关键 巨噬细胞功能。此外，sCD 163的研究可以确定一种治疗方法，以减轻O3诱导的 易受肺部感染。

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.