Periodontal inflammation is initiated by mucosal exposure to microbial organisms or their antigens. Mucosal epithelial cells, including those which line the oral cavity, have the capacity to modulate inflammatory responses to microbial infection, and do so with a high degree of fidelity. As part of the endogenous immune system, oral epithelia express of number of antimicrobial peptides, and recent studies indicate that endogenous lipid mediators generated during the resolution phase of inflammation promote epithelial protective responses to microbial products (e.g. endotoxin). At present, the mechanisms by which these resolution phase lipid mediators act are not known. Ongoing studies have revealed that oral epithelia express bactericidal permeability-increasing protein (BPI), a potent anti-infective molecule with microbial killing and endotoxin-neutralizing functions with previous expression attributed only to leukocytes. In preliminary data, we demonstrate that; a) oral epithelial BPI is functionally important in regulating epithelial responses to endotoxin and that resolution phase lipid mediators regulate epithelial expression of BPI. From these preliminary data, we hypothesize that epithelial antimicrobial peptides, including BPI, are central to mucosal resolution responses to microbial products during inflammation. Here, we will collaboratively pursue this hypothesis through three focused Specific Aims:
In Aim 1, we profile epithelial antimicrobial peptide regulation and function by resolution-phase lipid mediators.
In Specific Aim 2, we will define molecular details of resolution-phase lipid mediator regulation on oral epithelial antimicrobial expression.
In Aim 3, we will extend these findings to determine relevance of antimicrobial peptides to neutrophil-epithelial interactions. Each of these aims will incorporate a validation strategy in murine models and in human-derived materials. The long-term goals of this research are to elucidate the direct and indirect contribution of mucosal epithelia to inflammatory resolution Results from these experiments will reveal new insights into innate regulation of mucosal resolution and extensions of this work could lead to targets for experimental therapeutics.
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