Functional genomics of particle-induced lung injury

Currently the biological mechanisms controlling adverse reactions to partic ulate matter are uncertain, but are likely to include oxidative lung injury , inflammation, infection, and preexisting pulmonary disease (e.g., chronic obstructive pulmonary disease). Each mechanism can be viewed as a complex trait controlled by interactions of host (genetic) and environmental factor s. We propose that genetic factors play a major role in susceptibility to p articulate matter because the number of individuals exposed (even in occupa tional settings) is often large, but relatively few people respond with inc reases in morbidity and even mortality. Previous clinical studies support t his hypothesis, having discovered marked individual variation in diminished lung function following oxidant exposures. Advances in functional genomics have facilitated the examination of this hypothesis and have begun to prov ide valuable new insights into gene-environmental interactions. For example , genome-wide scans can be completed readily in mice that enable assessment of chromosomal regions with linkage to quantitative traits. Recently we an d others have identified linkage to oxidant-induced inflammation and mortal ity. Such linkage analysis can narrow and prioritize candidate gene(s) for further investigation, which, in turn, is aided by existing transgenic mous e models. In addition, differential expression (microarray) analysis enable s simultaneous assessment of thousands of genes and expressed sequence rags . Combining genome-wide scan with microarray analysis permits a comprehensi ve assessment of adverse responses to environmental stimuli and will lead t o progress in understanding the complex cellular,mechanisms and genetic det erminants of susceptibility to particulate matter.