Arsenic and Innate Immunity in Human Lung

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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.