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The purpose of this study was to investigate the proteomic mechanisms of Jet Propulsion-8 (JP-8) toxicity in the lung, specifically relating to lung epithelial cell apoptosis and edema. Male Swiss-Webster mice were exposed to 1 h/day aerosolized JP-8 jet fuel at concentrations of 250, 1000, and 2500 mg/m
3 for 7 days. Lung cytosol and whole lung samples were solubilized, separated via large scale, high-resolution two-dimensional electrophoresis, and processed for analysis. Significant quantitative differences in lung protein expression were found as a result of JP-8 exposure. At 250 mg/m
3 JP-8 concentration, 31 proteins exhibited increased expression, while 10 showed decreased expression. At 1000 mg/m
3 exposure levels, 21 lung proteins exhibited increased expression and 99 demonstrated decreased expression. At 2500 mg/m
3, 30 exhibited increased expression, while 135 showed decreased expression. Several of the proteins were identified by peptide mass fingerprinting, and were found to relate to cell structure, cell proliferation, protein repair, and apoptosis. These data demonstrate the significant stress JP-8 jet fuel puts on lung epithelium. Furthermore, there was a decrease in α1-anti-trypsin expression suggesting that JP-8 jet fuel exposure may have implications for the development of pulmonary disorders.