Lipid Mediators Derived from Docosahexaenoic Acid Alleviate Periodontal Inflammation and Alveolar Bone Loss in Periodontitis Associated with Suppression of the NF-κB and STAT3 Signaling Pathways

Background: Lipid mediators (LM), comprising 17S-hydroxy-docosahexaenoic acid, resolvin D5, and protectin DX in a ratio of 3:47:50, were naturally generated from docosahexaenoic acid by soybean lipoxygenase and exhibit potent anti-inflammatory activities. However, their therapeutic potential in periodontitis (PD) remains unclear. Therefore, this study investigated the protective effects of LM against PD in vitro and in vivo. Methods: Human gingival fibroblasts (HGFs) were stimulated with Porphyromonas gingivalis lipopolysaccharide (PG-LPS) to evaluate the anti-inflammatory effects of LM. Nitric oxide (NO) production, prostaglandin E2 (PGE2) level, inflammatory cytokines secretion, matrix metalloproteinase 9 (MMP9) expression, and NF-κB/STAT3 signaling pathways were analyzed. In vivo, a ligature-induced rat model of PD was established, and LM were orally administered at doses of 5, 10, and 20 μg/kg once daily. The effects of LM were evaluated by histopathological examination, micro-computed tomography (micro-CT), quantitative real-time PCR (qRT-PCR), and immunohistochemistry (IHC). Results: In PG-LPS-stimulated HGFs, LM significantly reduced NO and PGE2 production by downregulating inducible nitric oxide synthase and cyclooxygenase-2 expression. Moreover, LM decreased the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-1β, and MMP9, accompanied by suppression of the NF-κB and STAT3 signaling pathways. In the ligature-induced rat model of PD, LM significantly attenuated gingival inflammation and alveolar bone loss. Furthermore, IHC analysis revealed that LM markedly reduced the level of IL-6, TNF-α, MMP9, and phosphorylated STAT3 in gingival tissues. Conclusions: LM exerted protective effects against periodontitis by alleviating inflammatory response and reducing alveolar bone loss, which may be associated with suppression of the NF-κB and STAT3 signaling pathways.