GENETIC MECHANISMS OF OZONE TOXICITY IN THE MURINE LUNG

Johns Hopkins University, Baltimore MD

Investigators

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Abstract

DESCRIPTION: (Adapted from the investigator's abstract). Ozone (O3) is a highly reactive and toxic oxidizing pollutant that has become prevalent in urban environments. O3 exposure elicits inflammation, increase bronchial reactivity, reduces lung function and, in general, is a risk factor for respiratory health. Because of the impact that oxidant exposures may have on public health, identification of the intrinsic (host) factors that influence susceptibility to airborne pollutants remains an important issue. The potential contribution of genetic background as a host factor for susceptibility to oxidant air pollutant has been suggested but the nature of the genetic control is still unclear. To determine whether differential susceptibility to O3-induced pulmonary inflammation in inbred mice results from differences in the initial events of O3 injury or expression of pro-inflammatory candidate genes. The investigators have design four specific aims. In Aim 1, they will determine the kinetics of lung antioxidant and lipid ozonation product (LOP) formation in differentially O3-responsive B6 and C3 mice. In Aim 2, they will test the hypothesis that pulmonary macrophages from B6 and C3 mice express different LOP and mediator response profiles after in vivo and in vitro O3 exposure. In Aim 3, the investigators will test the hypothesis that O3-induced mRNA and protein expression of candidate genes TNFa and Sod-2 are differentially regulated by B6 and C3 mice. The investigators will also evaluate the role of TNF-alpha in regulation of other pro-inflammatory and antioxidant genes. In Aim 4, the investigators will test the hypothesis that O3-induced inflammation and epithelial injury co-segregate with expression of candidate genes (including Tnfa and Sod-2) in offspring derived from B6 and C3 mice. This proposal utilizes a multi-disciplinary approach that will provide unique insight into the genetic mechanisms that determine differential susceptibility to O3-induced inflammation. Inasmuch as there is close linkage homology between the mouse and human genomes, the identification of genes that control susceptibility to O3 in this model may provide a means to characterize individuals in human populations who are at risk to oxidant exposures.