Regulation of Platelet-activating Factor Acetylhydrolase During Inflammation

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DESCRIPTION (provided by applicant): Periodontitis is characterized as a chronic inflammatory disease triggered by pathogenic microbes and their products such as lipopolysaccharide.(LPS) The ensuing production of host inflammatory mediators contributes to disease progression and severity. Platelet-activating factor (PAF) is a potent inflammatory mediator that has been implicated in the progression of periodontal disease. A crucial mechanism in limiting the levels of PAF is the expression and activity of the enzyme involved in PAF degradation, PAF acetylhydrolase (PAF-AH). Our preliminary data demonstrates that PAF-AH expression is increased in response to inflammatory mediators. However, LPS isolated from the periodontal pathogen P. gingivalis may curtail this expression which could disturb the balance between PAF synthesis and degradation leading to a heightened inflammatory response. Our long-range research goals are to understand at the molecular level the dynamic relationship between inflammation and PAF-AH expression and activity as it pertains to periodontal disease. Two closely related Specific Aims will examine the regulation of PAF-AH in a human monocytic cell line in response to inflammatory mediators. Specifically, we will examine the expression and regulation of PAF-AH in response to stimulation with E. Coli LPS, two unique forms of P. gingivalis LPS, and from the inflammatory mediators PAF and TNF-1. Completion of the proposed Specific Aims will provide novel and important mechanistic information on how the host defense mechanism controls and limits inflammatory episodes. PUBLIC HEALTH RELEVANCE: Periodontitis is a chronic inflammatory disease that affects both oral and systemic health. Understanding the mechanism of regulation of an anti-inflammatory enzyme called platelet-activating factor acetylhydrolase will provide insight into the etiology of periodontal disease and potentially lead to novel therapeutic approaches.