Arsenic and Innate Immunity in Human Lung

项目3：摘要 砷（As）是美国最受关注的环境化学物质，对人类健康有重要影响。 流行病学研究表明，接触砷会增加肺部疾病，包括肺炎， 慢性阻塞性肺疾病在对实验动物的研究中，低水平的As抑制了 先天免疫系统，以消除呼吸道感染，并下调表达先天 免疫基因，但分子机制，其中作为抑制先天免疫系统是未知的。 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，委员会认为， 本申请的目的是检验无机和有机形式具有不同的剂量 通过不利地影响肺内的先天性 免疫反应这将在两个具体目标进行研究。具体目标1将检验以下假设： 亚砷酸、甲基胂酸（MMA）和二甲基胂酸（DMA）的浓度有差异， 对人支气管上皮（HBE）细胞分泌促炎细胞因子的影响， 巨噬细胞对Pa.将进行研究以检查亚砷酸盐、甲基丙烯酸甲酯和二甲基丙烯酸甲酯的影响， 在与美国人群相关的水平上，对暴露于Pa的HBE细胞和巨噬细胞产生细胞因子的影响。 具体目标#2将检验亚砷酸盐、MMA和DMA具有不同的剂量依赖性效应的假设 对HBE细胞和巨噬细胞响应Pa的促炎细胞因子基因表达的影响 选择性调节microRNA（miRNA）表达。利用先进的生物信息学和分子生物学 方法，将进行研究以阐明由As调节的miRNAs如何调节炎症反应。 回答Pa。这些研究将提供关于剂量和种属依赖性效应的新信息 亚砷酸盐，甲基丙烯酸甲酯和DMA，在相关的美国人口的水平，对免疫反应的Ps，病原体 在美国引起显著的发病率和死亡率，以及提供新的见解的分子 A调节人肺对Pa的先天免疫应答的机制。

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.