The proposed research plan will be pursued by a basic and physician scientist team interested in the development and testing of new drug strategies to treat airway inflammation and asthma. Preliminary data reveal that nitro (RNO2) and a,?-unsaturated keto (R=O) electrophilic fatty acid oxidation products (EFOX) are produced by inflammatory-activated macrophages and are present at increased concentrations in the airway lining fluids obtained by bronchoalveolar lavage of asthmatic patients. EFOXs are found in predominantly protein-adducted states (explaining why these species were just recently discovered), and are viewed as components of the adaptive response of organisms to inflammation. The investigators have observed that EFOX signal via both receptor-dependent mechanisms (as potent PPAR? ligands) and via electrophile-responsive transcription factor-regulated mechanisms. We intend to characterize the patterns and mechanisms of EFOX production during conditions relevant to airway inflammation in a) cultured airway epithelial cells and inflammatory cells, b) a murine model of asthma and c) sputum and lavage samples obtained from asthmatic patients. This endeavor will employ an unbiased HPLC-mass spectrometry-based "electrophile fishing" strategy. After learning more about the structural characteristics, concentrations and molecular targets of specific EFOXs in airway inflammation, we will evaluate the therapeutic potential of EFOXs in a murine model of asthma by in vivo administration of structurally identical synthetic compounds. The research strategy was designed to test the hypothesis that electrophilic nitro and keto derivatives of unsaturated fatty acids are formed by the oxidative inflammatory milieu of asthmatic airways and mediate anti-inflammatory cell signaling responses. This endeavor is of significance because it a) lends critical insight into fundamental molecular and cellular mechanisms leading to the generation of a new class of inflammatory-regulating species in asthma and b) tests a promising new endogenous mediator-based therapeutic approach for treating asthma patients that is amenable for rapid deployment as a clinical therapeutic strategy.
The proposed research plan will test a new anti-inflammatory drug strategy using clinically-relevant cell and animal models of asthma. Asthma places a considerable burden on US health care delivery and costs, with environmental factors increasing the prevalence of this condition. The proposed studies are significant because they lend additional insight into the molecular and cellular foundations of inflammatory events leading to asthma and have the promise to quickly make available a new therapeutic approach for treating asthmatic patients.
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