Oxidative Stress and Anti-Inflammatory Lipids in Airway Disease

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DESCRIPTION (provided by applicant): The proposed experiments will test the hypothesis that dysregulation of lipid mediator generation occurs in asthma and COPD. In response to infection, leukocytes and tissue-resident cells interact to generate lipid mediators that enhance the airway's immune responses and engage anti-microbial host defense mechanisms. Microbial killing and restoration of airway homeostasis is an active process coordinated by specific mediators and cellular events. Leukocyte activation leads to the generation of lipid mediators with potent biological actions that serve to enhance the airway's immune responses and engage anti-microbial host defense mechanisms. Leukotrienes (LTs) and prostaglandins (PGs) are rapidly generated to enhance leukocyte responses. Lipoxin (LX) formation is temporally delayed, yet ultimately critical for mucosal host defense and control of infection and pathogen- mediated inflammation. Unlike PGs and LTs that are principally generated from arachidonate within single cells for subsequent release, LX biosynthesis occurs during cell-cell interactions. The extracellular exchange of LX biosynthetic intermediates between cells lends these pathways vulnerable to oxidative stress that would disrupt LX formation and favor the generation of alternate products, such as F2-isoprostanes, that display pro-phlogistic rather than LXs' counter-regulatory properties. Decreased LX generation has recently been identified in several diseases of airway inflammation, including severe asthma, which like COPD exacerbations, is associated with increased oxidative stress. Thus, increased oxidative stress in the airway may predispose to diminished formation of host protective, counter-regulatory lipid mediators and thereby an increased susceptibility for airway infection or inflammation. To test our hypothesis, we propose three specific aims to determine: To profile relationships between enzymatic and non-enzymatic oxygenation of fatty acid substrates, To determine the generation of lipoxins and related counter-regulatory lipid mediators during chronic airway infection in asthma, To measure the time course for lipoxin and related counter-regulatory lipid mediator biosynthesis during acute COPD exacerbation and resolution. This proposal's specific aims are directed towards uncovering the basis for susceptibility to airway infection and inflammation, identifying novel biomarkers and developing new therapeutic strategies for asthma and COPD. Exacerbations are the most serious expression of asthma and COPD, common respiratory ailments that affect the lives of millions of Americans. Even with the proper use of bronchodilators, corticosteroids and other currently available medications, clinical responses are variable. Consequently, there remains a significant unmet clinical need for new insights. Some individuals with asthma or COPD display an inherently increased susceptibility for airway infection that is only transiently addressed with antibiotics. In this proposal, we seek to develop a better understanding of the natural biological processes invoked during airway infection and inflammation that dysregulate the natural homeostatic mechanisms. (End of Abstract)