Novel Lipid Mediators in Periodontal Disease Resolution Circuits

如发生生物恐怖袭击时，“不受控制”的急性炎症可导致对个人生命的巨大威胁和对公共卫生的不当风险。人中性粒细胞（PMN）通过释放影响组织完整性和口腔功能的脂质衍生介质（LM）和促炎产物，在急性炎症和牙周病（PD）相关的组织损伤中发挥关键作用。来自PI实验室的新证据和正在进行的工作表明，在溶解过程中对PMN的控制是一个积极的过程，在渗出物中发现了由PMN产生的有效的新型保护性LM，称为溶解素（RV）和docosatrienes (DT)，可减少急性炎症和PMN介导的组织损伤。从

Acute inflammation when "uncontrolled" can lead, as in the event of bioterrorist attacks, to massive threat to individual life and undue risk to public health. Human neutrophils (PMN) play pivotal roles in acute inflammation and periodontal disease (PD)-associated tissue injury by releasing lipid-derived mediators (LM) and pro-inflammatory products that affect both tissue integrity and oral function. New evidence has emerged from the PI's laboratory and work in progress indicating that control of PMN during resolution is an active process with the identification in exudates of potent novel protective LM termed resolvins (RV) and docosatrienes (DT) generated by PMN that reduce acute inflammation and PMN-mediated tissue injury. From these findings, it is now clear that the molecular map of resolution, an important homeostatic process, remains largely uncharted. The focus of sub-project 0001 in this multi-disciplinary Specialized Center for Research is on systematic elucidation of novel pro-resolving circuits using lipidomics coupled with proteomics. Sub-Project 0001 will test the hypothesis that LM, including RV, DT, and their aspirin-triggered epimers, regulate endogenous anti-inflammatory circuits that govern leukocyte traffic and key molecular events required for resolution. Disruption of these novel resolution circuits by microbial products and widely used treatments in oral surgical practices (local anesthetics, NSAIDs) prolongs tissue inflammation. To test this, 3 specific aims are proposed: Aim 1 will establish the formation and role of LM and molecular circuitry of resolution in murine peritonitis compared to PD with the directive of translating identified resolution components to humans via Core 9002. Experiments in Aim 2 are designed to identify the LM receptors involved in resolution of PD using genetically engineered mice, and labeled-RV and DT with both human PMN and recombinant receptors. Aim 3 will determine the impact of microbe products, current anti-inflammatories, and local analgesics in timely resolution. The broad long-term goals are two-fold: 1) elucidate the human map of oral resolution and associated genes evoked during microbial defense and PMN-mediated tissue injury in PD, and 2)provide map(s) with molecular coordinates of resolution to oral surgeons and dentists to improve current treatment practices and preparedness for bioterrorist attacks.