Application of quantitative structure activity relationship (QSAR) models to predict ozone toxicity in the lung.

The sequence of events leading to ozone-induced airway inflammation is not well known. To elucidate the molecular and cellular events underlying ozone toxicity in the lung, we hypothesized that lipid ozonation products (LOPs) generated by the reaction of ozone with unsaturated fatty acids in the epithelial lining fluid and cell membranes play a key role in mediating ozone-induced airway inflammation. To test our hypothesis, we ozonized 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) and generated LOPs. Confluent human bronchial epithelial cells were exposed to the derivatives of ozonized POPC-9-oxononanoyl, 9-hydroxy-9-hydroperoxynonanoyl, and 8-(5-octyl-1,2,4-trioxolan-3-yl-)octanoyl-at a concentration of 10 muM, and the activity of phospholipases A2 (PLA2), C (PLC), and D (PLD) was measured (1, 0.5, and 1 h, respectively). Quantitative structure-activity relationship (QSAR) models were utilized to predict the biological activity of LOPs in airway epithelial cells. The QSAR results showed a strong correlation between experimental and computed activity (r = 0.97, 0.98, 0.99, for PLA2, PLC, and PLD, respectively). The results indicate that QSAR models can be utilized to predict the biological activity of the various ozone-derived LOP species in the lung.