RESOLUTION OF CYTOKINE-MEDIATED SALIVARY GLAND INFLAMMATION

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ABSTRACT Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease characterized by diminished secretory function of the exocrine glands. Treatments for hyposalivation are limited to use of saliva substitutes and medications that provide only temporary relief. In light of the high degree of need and the limitations of current therapies, development of alternative treatments to restore functioning is essential. Resolvins (Rv), which are which are highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. Results from our previous funding period demonstrated the following: a) salivary glands express the RvD1 and AT-RvD1 receptor (ALX/FPR2); b) activation of ALX/FPR2 blocks pro-inflammatory cytokine signaling, thereby promoting cell survival and tissue integrity in salivary cells; c) RvD1 biosynthetic pathways are functional in salivary epithelium; d) loss of ALX/FPR2 results in unresolved inflammation and SMG dysfunction in vivo; e) AT-RvD1 treatment in SS-like NOD/ShiLtJ mice fully preserves secretory functioning, downregulates pro-inflammatory cytokine expression and promotes pro-resolving signaling pathways; f) treatment combining AT-RvD1 and dexamethasone (DEX) reduces salivary gland lymphocytic infiltration in comparison to AT-RvD1 alone, g) a three-dimensional culture system using human SMG cells was optimized for the study of ALX/FPR2 signaling and h) human saliva was demonstrated to express resolvin lipid mediators. Promising though these findings may be, however, we face significant issues that must be overcome for the clinical application of resolvins to be achieved. Specifically, resolvins (RvD1 included) do not reach their intended destination with desired regularity because they are quickly inactivated by eicosanoid oxidoreductases or EORs upon introduction to the body, have a short plasma half-life (approximately 3 h) and have effects that are spread throughout the body (such that they cannot specifically target inflamed areas, as would be needed for optimal treatment of inflammatory diseases). Furthermore, the problem of instability extends to the AT forms, which are somewhat less susceptible to inactivation but still demonstrate less than ideal stability. However, we believe that all of these issues may be addressed by use of elastin-like polypeptide nanoparticles (iTEP NPs), which are biocompatible micelle-like molecules engineered to contain AT-RvD1. Specifically, iTEP NPs are capable of protecting AT-RvD1 from inactivation, increasing plasma half-life and easily permeating inflamed blood vessels, thereby allowing them to congregate in areas of inflammation. The main goal of this proposal is to determine whether SS symptoms can be reduced by AT-RvD1 treatment. Aim 1: will demonstrate the utility of AT-RvD1 treatment in the NOD/ShiLtJ SS mouse model. Aim 2: will translate AT-RvD1 treatment to human salivary cells and Aim 3: will enhance AT-RvD1 treatment through a delivery system using iTEP NPs.