The overall goals of this project are to determine how selected Superfund chemicals influence immunity and inflammation and to understand the mechanisms and potential health consequences of such effects.
The aims for the next granting period were driven by a need for knowledge of interactions among chemicals and the specific and nonspecific components of the immune system. Specific hypotheses to be tested derive from the recent findings of the investigators of the three subprojects. Research in this Subproject has revealed that PCB mixtures activate rat neutrophils (PMNs) in vitro to release toxic oxygen metabolites and lysosomal enzymes and also influence the response to other PMN stimuli. In vivo, PCB treatment increases hepatotoxicity in a rat model of PMN- dependent liver injury. The mechanism by which PCBs affect PMNs appears to be independent of the Ah receptor and involves altered hydrolysis of phosphoinositides and dependence on extracellular calcium. Future studies will focus on further examination of signal transduction in PMNs to identify the intracellular target(s) of PCBs and on the potential health consequences of PCB-PMN interactions in vivo. The studies proposed in this Project will employ cellular, isolated organ and whole animal models and entail molecular, biochemical and morphologic methods that include techniques such as cell imaging and flow cytometry. Accomplishing goals of this Project as well as aiding in the toxicologic evaluation of products of remediation will involve considerable interaction not only among project investigators but also with investigators of other projects and cores. Results from these studies will increase understanding of the mechanisms and potential health consequences of interactions of Superfund chemicals with the immune system.
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