Mechanisms of Pro-Resolving Mediators in Periodontal Regeneration

点击翻译按钮获取中文摘要

Dietary supplementation with the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for improving prevention or outcomes of inflammatory diseases, including periodontitis, has been suggested and supported in the literature. However, there remains a critical need to characterize their mechanism of action to optimize the use of nutritional supplements to benefit the population. There are major gaps in knowledge as it pertains to the mechanisms by which EPA and DHA exert their functional effects. Mechanistically, EPA and DHA supplements in the diet increase the concentration of downstream hydroxylated-EPAs (HEPEs) including 18-HEPE, and hydroxylated-DHAs including 17-HDHA, which are bioactive compounds. 18-HEPE and 17-HDHA are also the precursors for the immunoresolvents known as E-series and D-series resolvins, respectively, which improve periodontal disease outcomes through the activation of specific receptors on stem cells. There remain major gaps in our understanding of the mechanistic relationship between stem cell dysfunction and periodontitis. Our data lead us to the hypothesis that dietary supplementation with EPA and DHA, or their HEPE/HDHA metabolites, will have an impact on treatment outcomes for periodontitis, in part, through the activation of the resolvin/stem cell receptor axis. We will test the hypothesis using a combination of EPA/DHA- and HEPE/HDHA- based dietary supplements in our pig model of stem cell enhanced periodontal regeneration measuring clinical outcomes and investigating mechanism using cutting-edge mass spectrometry-based approaches and assessments of SPM receptor expression and function. Overall, the proposed research will provide much needed clarity to the field of n-3 PUFAs and periodontal disease. The data will specifically provide a scientific rationale for future precision clinical trials with dietary supplements for periodontitis treatment and prevention. The Central Hypothesis is that dietary supplements containing EPA/DHA or HEPE/HDHA precursors of resolvins will enhance resolution of inflammation pathways and mediator production to promote regeneration of the periodontal organ (bone, cementum, and periodontal ligament) by directing stem cell phenotype, proliferation, and differentiation. In this supplement, we will use our ongoing large-animal model experiments to dissect the impact of dietary supplements on the SPM pathways leading to periodontal ligament stem cell control of regeneration. In the miniature pig periodontal regeneration experiments, we will determine whether dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors enhances periodontal regeneration alone or in combination with transplanted, ex vivo expanded miniature pig stem cells and determine the impact of dietary supplementation with EPA/DHA or concentrated HEPE/HDHA resolvin precursors on systemic (blood) and local tissue levels of pro-inflammatory and proresolving lipid mediators. These experiments are critical and focused to determine the potential of dietary supplementation with n-3 PUFAs for periodontal regeneration.