Bioactive lipid mediators and reactive oxygen species

National Jewish Health, Denver CO

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Abstract

Ozone is a reactive oxygen species that reacts with lipids in the pulmonary airways and initiates a complex inflammatory response even when breathed at low concentrations. Ozone is also one of the important environmental pollutants that is present in urban population (less than 300 ppb) known to execerbate lung inflammation in susceptible individuals. A major hypothesis to be tested is that low concentrations of ozone are particularly damaging to individuals with existing lung disease due to an applification of the inflammatory response caused by ozone generated bioactive lipids, which could have a synergistic effect on ongoing pulmonary cell activation. The specific model to be examined will be the effect of ozone derived lipids on the response of macrophages to apoptotic cells and to cells that have phagocytized Candida albicans. The structural analysis and quantitation of lipid mediators derived from reaction of ozone with endogenous lipids requires the development of sophisticated yet nonspecific analytical techniques capable of providing specific data for lipids even though they are present in complex mixtures of closely related compounds. Mass spectrometry is such a tool. The major objective of this grant is to further understand the mechanism by which ozone can alter the inflammatory response in the lung through generation of bioactive lipid products. Specific responses of cells relevant to the lung (alveolar macrophage) will be studied when lung surfactant is exposed to low concentrations of ozone. These responses will be used to guide isolation and purification of lipid products that will be structurally characterized using mass spectrometry. The potential for mass spectrometry as a tool used for imaging lipids in tissues will also be investigated with the Intent of applying mass spectrometric imaging to determine the precise localization of ozone generated novel lipid products in pulmonary airways following exposure of mice to environmentally relevant concentrations of ozone. The specific goal is to understand the molecular basis underline the toxicity of ozone in lung. The oxidation of cholesterol by ozone and the formation of active oxysterols will be further examined. The reaction of ozone with plasmalogen glycerophospholipids will also be investigated in studies to test the hypothesis that vinyl ether phospholipids serve as an important precursor of bioactive lysophospholipids.