Sunday, May 5, 2024
5/5/2024
PROJECT SUMMARY (ABSTRACT) Ozone (O3) is a harmful air pollutant that exacerbates chronic lung diseases in part by activating inflammatory responses, inducing lung injury, and inhibiting resolution mechanisms. Resolution mechanisms are mediated largely by specialized pro-resolving mediators (SPMs). SPMs are potent bioactive molecules that inhibit immune cell recruitment, downregulate pro-inflammatory cytokine and chemokine production, and upregulate phagocytosis of apoptotic cells – a resolution process termed ‘efferocytosis’. We have previously reported that O3 decreases SPM production and inhibits efferocytosis, potentially contributing to exacerbated and persistent inflammation observed in patients with pulmonary diseases exposed to O3. SPMs are metabolized primarily from ¿-3 fatty acids, such as docosahexaenoic acid (DHA). DHA can be consumed through diet or, more commonly in western cultures, synthesized from the essential fatty acid a-linolenic acid by elongation of very long-chain fatty acids protein 2 (ELOVL2). Preliminary data in this proposal indicates that DHA concentrations and ELOVL2 expression increase in the lung tissue following O3 exposure. Furthermore, ELOVL2 is increased in alveolar macrophages (AMs) after O3 exposure, suggesting an immunological need for endogenous DHA in AMs. When exogenous DHA was supplemented through diet, the O3-induced pulmonary and AM driven inflammatory responses were reduced, AM efferocytosis was augmented, and markers of lung injury resolved faster. Additionally, similar findings were noted when mice were pretreated with DHA derived SPM intermediates that correlated with an increase in the SPM maresin 1 (MaR1) in lung tissue. MaR1 is a unique SPM that is primarily produced by monocytes and macrophages that binds to leucine rich repeat containing G protein-coupled receptor 6 (LGR6) to facilitate resolution processes. To examine MaR1 signaling following O3 exposure, we measured LGR6 expression on AMs and found it to be significantly reduced when pulmonary inflammation was ongoing. Taken together, these data indicate that endogenous DHA in AMs leading to MaR1 signaling may be a crucial pathway to resolving O3-induced lung injury and inflammation. Therefore, we hypothesize that endogenous DHA synthesis in AMs is required for production of MaR1 which reduces the severity and improves resolution of O3-induced lung inflammation . To test this hypothesis, we will: 1) Examine how endogenous DHA synthesis via ELOVL2 in AMs reduces O3-induced pulmonary inflammation and promotes resolution responses, and 2) Determine if DHA-derived MaR1 signaling induces a pro-resolving AM phenotype through LGR6, mitigating pulmonary inflammation and promoting resolution following O3 exposure. Completion of the proposed aims and training included in this proposal will prepare the applicant for a successful career as an independent investigator and will equip him with cutting edge techniques, a strong network of mentors, and didactic training required for a successful career in academia.
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