Resolvin D1 Improves the Resolution of Inflammation via Activating NF-κB p50/p50-Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a severe illness characterized by uncontrolled inflammation. The resolution of inflammation is a tightly regulated event controlled by endogenous mediators, such as resolvin D1 (RvD1). Cyclooxygenase-2 (COX-2) has been reported to promote inflammation, along with PGE₂, in the initiation of inflammation, as well as in prompting resolution, with PGD₂ acting in the later phase of inflammation. Our previous work demonstrated that RvD1 enhanced COX-2 and PGD₂ expression to resolve inflammation. In this study, we investigated mechanisms underlying the effect of RvD1 in modulating proresolving COX-2 expression. In a self-limited ARDS model, an LPS challenge induced the biphasic activation of COX-2, and RvD1 promoted COX-2 expression during the resolution phase. However, it was significantly blocked by treatment of a NF-κB Inhibitor. In pulmonary fibroblasts, NF-κB p50/p50 was shown to be responsible for the proresolving activity of COX-2. Additionally, RvD1 potently promoted p50 homodimer nuclear translocation and robustly triggered DNA-binding activity, upregulating COX-2 expression via lipoxin A₄ receptor/formyl peptide receptor 2. Finally, the absence of p50 in knockout mice prevented RvD1 from promoting COX-2 and PGD₂ expression and resulted in excessive pulmonary inflammation. In conclusion, RvD1 expedites the resolution of inflammation through activation of lipoxin A₄ receptor/formyl peptide receptor 2 receptor and NF-κB p50/p50-COX-2 signaling pathways, indicating that RvD1 might have therapeutic potential in the management of ARDS.