The reaction of NO and NO-derived species with oxidizing lipids is kinetically rapid and exerts a multifaceted impact on cell and inflammatory signaling. NO-derived species have been shown to induce the nitration of polyunsaturated fatty acids, yielding allylic nitro derivatives (LNO2) that display receptor-ligand interactions, regulate the gene expression and tissue content of key inflammatory and cell signaling-related proteins and inhibit inflammatory cell function. Thus, nitrated lipids represent both products and mediators of inflammatory reactions. Since the lung is a rich source and vulnerable target of oxides of nitrogen, we propose to identify the generation and cell signaling actions of the principal nitrated lipids present basally and during clinically-relevant conditions of pulmonary inflammation, inhalation of oxides of nitrogen (NO and NO2) and exposure to gases that influence pulmonary oxidative/nitrative reactions (O2 and CO2). The hypothesis guiding the proposed research plan is that pulmonary exposure to NO-derived inflammatory oxidants yield nitrated lipid derivatives that modulate the resolution of pulmonary inflammation. The following Specific Aims will be pursued: 1. Quantify and characterize nitrated fatty acids in pulmonary cells and lung tissue. 2. Evaluate the mechanisms underlying the accumulation of pulmonary fatty acid nitration products. 3. Explore pulmonary cell signaling responses to nitrated fatty acids. The proposed research plan has thus been designed to focus on lipid reactions of NO and its products under biologically-, clinically- and toxicologically-relevant conditions and to define key signaling properties of nitrated lipid products in oxidative inflammatory lung injury and its resolution.
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