resolvin-d1 and Xerostomia

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 the 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 highly potent lipid mediators, offer a viable alternative for better treating inflammatory diseases such as SS. The goal of this study was to determine whether systemic preventive treatment with Aspirin-triggered RvD1 (AT-RvD1) reduces inflammation and preserves secretory functioning in NOD/ShiLtJ SS-like mice. Our results indicate that systemic treatment with AT-RvD1 diminishes the progression of the disease in salivary epithelium from female mice as follows: (a) improves secretory function, (b) reduces pro-inflammatory molecule gene expression, (c) increases anti-inflammatory molecule gene expression and (d) induces M2 macrophage polarization. Finally, AT-RvD1 decreases lymphocytic infiltration into the salivary glands when used with small doses of the steroid, dexamethasone, and promotes the tissue healing process.

Topics: Animals; Aspirin; Dexamethasone; Docosahexaenoic Acids; Epithelium; Female; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Salivary Glands; Sjogren's Syndrome; Xerostomia

Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A4 and resolvin D1 (RvD1) promotes resolution of inflammation. Our previous in vitro studies indicate that RvD1 activation of ALX/FPR2 resolves cytokine-mediated inflammatory responses in mammalian cells. However, the impact of ALX/FPR2 activation on salivary gland function in vivo is unknown. The objective of this study was to determine whether submandibular glands (SMG) from ALX/FPR2(-/-) mice display enhanced inflammatory responses to lipopolysaccharides (LPS) stimulation. For these studies, C57BL/6 and ALX/FPR2(-/-) mice at age 8-12-week-old were treated with LPS by i.p for 24 h. Salivary gland structure and function were analyzed by histopathological assessment, saliva flow rate, quantitative PCR, Western blot analyses and immunofluorescence. Our results showed the following events in the ALX/FPR2(-/-) mice treated with LPS: a) upregulated inflammatory cytokines and decreased M3R (Muscarinic Acetylcholine receptor M3) and AQP5 (Aquaporin 5) protein expression, b) decreased saliva secretion, c) increased apoptosis, d) alteration of tight junction and neuronal damage. Overall, our data suggest that the loss of ALX/FPR2 results in unresolved acute inflammation and SMG dysfunction (xerostomia) in response to LPS that is similar to human salivary gland dysfunction induced by bacterial infection.

Topics: Animals; Apoptosis; Aquaporin 5; Cytokines; Docosahexaenoic Acids; Down-Regulation; Female; Inflammation; Leukocytes; Lipopolysaccharides; Lipoxins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Receptor, Muscarinic M3; Receptors, Formyl Peptide; Submandibular Gland; Tight Junctions; Up-Regulation; Xerostomia