A pathological hallmark of mucosal inflammatory processes is the accumulation of large numbers of polymorphonuclear leukocytes (PMN). For successful transmigration, PMN must traverse the epithelial barrier. A present, the signals which recruit PMN to epithelial surfaces, as well as biochemical crosstalk pathways at such loci, remain unclear. The long term objective of this proposal is to achieve a precise understanding of the molecular events regulating PMN interactions with oral epithelia (OE). Preliminary data reveal that pathways utilized by PMN to migrate across OE differ from those of other mucosal epithelia. Using a novel monoclonal antibody directed against an OE surface molecule important for PMN transmigration, we will dissect the molecular events regulating PMN-OE interactions. During PMN interactions with epithelia, PMN- liberated, soluble 5'AMP is converted to adenosine through the action of epithelial expressed 5'-ecto-nucleotidase (CD73). Our preliminary data revealed that oral epithelial cells express the A2a adenosine receptor subtype. Adenosine receptors A2a and A2b are reported to increase the intracellular levels of cAMP, a condition which promotes epithelial barrier function. The precise mechanism behind cAMP-induced promotion of barrier function has long remained elusive. This proposal will investigate the role of adenosine signaling with respect to PMN-OE interactions. Finally, using OE transfected with mutant forms of vasodilator-stimulated phosphoprotein (VASP), the precise role of VASP in regulating oral epithelial barrier function will be examined. Successful completion of these aims will provide the basis for development of novel, effective treatments for mucosal inflammation, such as occurs in periodontitis.
| Colgan, Sean P; Comerford, Katrina M; Lawrence, Donald W (2002) Epithelial cell-neutrophil interactions in the alimentary tract: a complex dialog in mucosal surveillance and inflammation. ScientificWorldJournal 2:76-88 |
