Air Pollution and Microvascular Dysfunction: Leukocyte-Dependent NAD(P)H Oxidase

空气污染和微血管功能障碍：白细胞依赖性 NAD(P)H 氧化酶

• 批准号: 8063859
• 负责人: Qinghua Sun
• 金额: $ 12.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063859
• 关键词: Acetylcholine; Acute; Air Pollution; Animal Model; Antibodies; Atherosclerosis; Biological; Biological Models; Blood Vessels; Breathing; Caliber; Cardiovascular system; Cells; Confocal Microscopy; Endothelium; Epidemiologic Studies; Event; Exposure to; Flow Cytometry; Functional disorder; Generations; Genes; Hypertension; Inflammation; Inflammatory Response; Knockout Mice; Leukocyte Rolling; Leukocyte Trafficking; Leukocytes; Link; Measures; Mediating; Membrane; Microcirculation; Modeling; Molecular; Mouse Protein; Mus; Nitric Oxide; Oxidases; Particulate Matter; Pathway interactions; Phenylephrine; Play; Principal Component Analysis; Production; Proteins; Reactive Oxygen Species; Research Personnel; Role; Serotonin; Sorting - Cell Movement; Source; Superoxides; System; Technology; Testing; Time; Tiron; Tissues; Transgenic Mice; Vasoconstrictor Agents; Vasodilator Agents; Whole Blood; air filter; base; c-fms Proto-Oncogenes; constriction; human NOS3 protein; inhibitor/antagonist; intravital microscopy; macrophage; monocyte; mouse model; neutrophil; promoter; response; vascular inflammation

DESCRIPTION (provided by applicant) Epidemiological studies have demonstrated an association between fine particulate matter (PM2.5) and acute cardiovascular events. While the precise mechanism(s) that result in transduction of responses to inhaled PM2.5 in the vasculature are currently not well understood, it is clear that these responses can occur within a few weeks of exposure. To investigate the mechanisms by which PM2.5may modulate inflammation and vascular tone with short-term exposure, the researchers will investigate these responses in relevant animal models using real world ambient PM2.5 exposure. Accordingly, they hypothesize that exposure to ambient PM2.5 for 8 weeks induces systemic microvascular inflammation and dysfunction through monocyte/macrophage NAD(P)H dependent reactive oxygen species (ROS) generation and that endothelial nitric oxide plays a pivotal role in modulation of these responses. The investigators plan to examine this hypothesis systematically in appropriate animal model systems that will include genetically modified and tissue-specific conditional gene knockout mice via Cre-lox technology using a versatile ambient exposure system. In the first specific aim, they will investigate the effect of 8-week exposure to PM2.5 in FVBN mice and endothelial nitric oxide synthase (eNOS) knockout mice and examine leukocyte and vascular responses and superoxide production in cremasteric microcirculation. In the second specific aim, the investigators will determine the activation of monocyte/macrophage NAD(P)H oxidase in mice expressing enhanced yellow fluorescent protein (YFP) under the control of c-fms promoter after PM2.5 exposure by flow cytometry, intravital microscopy, and real time PCR. In the final specific aim, they will investigate the effect of PM2.5 exposure on NAD(P)H oxidase derived ROS-mediated monocyte response in the microcirculation in the mice deficient in a critical cytosolic component of NAD(P)H oxidase (p47phox-/- or gp91phox-/-) and tissue specific (endothelium or monocyte/macrophage lineage), conditional gene knockout mice models. Principal component analysis of PM2.5 will also be performed to elucidate which source-related components are most closely associated with biological responses. This study is expected to provide the link between PM2.5 exposure and systemic inflammatory response, and will provide a cellular and molecular basis for the association of adverse cardiovascular effects with air pollution exposure.

描述（由申请人提供） 流行病学研究表明，细颗粒物（PM2.5）与急性心血管事件之间存在关联。尽管目前尚不清楚导致对脉管系统中吸入的PM2.5的反应转导的确切机制，但很明显，这些反应可能会在暴露的几周内发生。为了调查PM2.5MAY通过短期暴露调节炎症和血管张力的机制，研究人员将使用现实世界环境PM2.5暴露在相关动物模型中调查这些反应。 因此，他们假设暴露于8周的环境PM2.5会诱导全身性微血管炎症和通过单核细胞/巨噬细胞NAD（P）H依赖性活性氧（ROS）产生的，并且内皮硝酸氧化物在这些反应的调节中起着重要作用。 研究人员计划在适当的动物模型系统中系统地检查这一假设，其中包括通过多功能环境暴露系统通过CRE-LOX技术进行转基因和组织特异性的条件基因敲除小鼠。 在第一个特定目的中，他们将研究在FVBN小鼠中暴露于PM2.5的8周和内皮一氧化氮合酶（ENOS）敲除小鼠的影响，并检查白细胞和血管反应以及在刺刺激性微循环中产生的白细胞反应以及超氧化物的产生。 在第二个特定目的中，研究人员将在PM2.5在通过流式细胞仪，弹药显微镜，弹药显微镜和实时PCR下暴露后的C-FMS启动子控制下，在C-FMS 2.5暴露后，在C-FMS启动子的控制下表达增强的黄色荧光蛋白（YFP）的小鼠中单核细胞/巨噬细胞NAD（P）H氧化酶的激活。 在最终的具体目标中，他们将研究PM2.5暴露对NAD（p47phox p47phox的NAD（P）H氧化酶的关键胞质成分中的小鼠中NAD（P）H氧化酶在微循环中的NAD（P）H氧化酶的作用（P47phox - / - 或GP91Phox - / - / - / - / - / - / - / - / - / - / - / - / - / - 或单位）（endothe）或模e（Endophox）或单位元素（Endotheel centore）（endothe）（p）敲除小鼠模型。还将对PM2.5进行主成分分析，以阐明哪些与源相关的成分与生物学反应最紧密相关。 预计这项研究将提供PM2.5暴露与全身性炎症反应之间的联系，并将为不良心血管效应与空气污染暴露的关联提供细胞和分子基础。

项目成果

Kupffer cell activation by ambient air particulate matter exposure may exacerbate non-alcoholic fatty liver disease.

环境空气颗粒物暴露引起的库普弗细胞激活可能会加剧非酒精性脂肪肝。

• DOI: 10.1080/15476910903241704
• 发表时间: 2009
• 期刊: Journal of immunotoxicology
• 影响因子: 3.3
• 作者: Tan,Hui-Hui;Fiel,MIsabel;Sun,Qinghua;Guo,Jinsheng;Gordon,RonaldE;Chen,Lung-Chi;Friedman,ScottL;Odin,JosephA;Allina,Jorge
• 通讯作者: Allina,Jorge