Arsenic and Innate Immunity in Human Lung

项目3：摘要 在美国，砷(As)是与人类健康有关的头号环境化学品。 流行病学研究表明，接触砷会增加肺部疾病，包括肺炎，以及 慢性阻塞性肺病。在对实验动物的研究中，低水平的砷抑制了 先天免疫系统能消除呼吸道感染，并下调先天基因的表达 免疫基因，但AS抑制先天性免疫系统的分子机制尚不清楚。 此外，无机砷与有机砷对先天免疫系统的影响尚不清楚。因此， 这一应用的目标是检验无机和有机形态具有不同剂量的假设。 肺部铜绿假单胞菌感染对先天感染的依赖作用 免疫反应。这将在两个具体目标下进行调查。第一个具体目标将检验这一假设 亚砷酸盐、一甲基砷酸(MMA)和二甲基砷酸(DMA)具有不同的剂量依赖性 对人支气管上皮细胞分泌促炎细胞因子的影响 巨噬细胞对PA的反应。将进行研究，以检查亚砷酸盐、MMA和DMA的影响， 在与美国人口相关的水平上，对暴露于PA的HBE细胞和巨噬细胞产生细胞因子的影响。 特殊目标#2将检验亚砷酸盐、甲基丙烯酸甲酯和二甲基亚硝胺具有不同的剂量依赖效应的假设 PA对HBE细胞和巨噬细胞促炎细胞因子基因表达的影响 选择性地调节microRNA(MiRNA)的表达。利用先进的生物信息学和分子生物学 方法，将进行研究，以阐明AS调节的miRNAs如何调节炎症 对爸爸的回应。这些研究将提供有关剂量和物种依赖效应的新信息。 亚砷酸盐、MMA和DMA在与美国人口相关的水平上对病原体Ps的免疫反应 这在美国导致了显著的发病率和死亡率，并为分子生物学提供了新的见解 AS调节人肺对PA的先天免疫反应的机制(S)。

Project 3: Abstract Arsenic (As) is the number one environmental chemical of concern with regard to human health in the US. Epidemiological studies have shown that exposure to As increases lung disease, including pneumonia, and chronic obstructive pulmonary disease. In studies on experimental animals low levels of As inhibit the ability of the innate immune system to eliminate respiratory infections, and down regulate the expression of innate immune genes, but the molecular mechanisms whereby As inhibits the innate immune system is unknown. Moreover, the effects of inorganic versus organic As on the innate immune system is unknown. Accordingly, the goal of this application is to test the hypothesis that inorganic and organic forms have differential, dose dependent effects on the Pseudomonas aeruginosa (Pa) infections in the lung by adversely affecting the innate immune response. This will be investigated in two specific aims. Specific Aim #1 will test the hypothesis that arsenite, monomethylarsonic acid (MMA) and dimetheylarsinic acid (DMA) have differential, dose dependent effects on the secretion of proinflammatory cytokines by human bronchial epithelial (HBE) cells and macrophages in response to Pa. Studies will be conducted to examine the effects of arsenite, MMA and DMA, at levels relevant to the US population, on cytokine production by HBE cells and macrophages exposed to Pa. Specific Aim #2 will test the hypothesis that arsenite, MMA and DMA have differential, dose dependent effects on the expression of proinflammatory cytokine genes by HBE cells and macrophages in response to Pa by selectively regulating microRNA (miRNA) expression. Using advanced bioinformatic and molecular biological approaches, studies will be conducted to elucidate how miRNAs regulated by As modulate the inflammatory response to Pa. These studies will provide novel information regarding the dose and species dependent effects of arsenite, MMA and DMA, at levels relevant to the US population, on the immune response to Ps, a pathogen that causes significant morbidity and mortality in the US, as well as provide novel insight into the molecular mechanism(s) whereby As modulates the innate immune response of the human lung to Pa.