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

Abstract

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.

Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19

“…Furthermore, stimulated alveolar macrophages had reduced concentrations of ARA-derived mediators, such as PGE2 and TXB2, suggesting a beneficial effect of omega-3 fatty acids over omega-6 fatty acids in ALI attenuation [77,78]. More recently, the role of SPMs, specifically resolvins, in the resolution of inflammation has been demonstrated in several animal models of ALI and ARDS [79][80][81][82]. These studies, carried out using rats and mice models infected with E.coli O55:B5 endotoxin LPS, suggested that the pro-resolving effects of these molecules could be attributed, for example, to the suppression of neutrophil infiltration due to reduction of expression and release of pro-inflammatory cytokines from alveolar macrophages [79,81].…”

Optimal Nutritional Status for a Well-Functioning Immune System Is an Important Factor to Protect against Viral Infections

“…This could be very important in the context of severe COVID-19 which manifests as uncontrolled inflammation, the so-called cytokine storm [18,19], linked with acute respiratory distress syndrome (ARDS). A number of the SPMs formed from EPA and DHA have been shown in animal models to both protect against and resolve acute lung injury and ARDS [20][21][22][23][24]. Nutritional formulas containing antioxidants and rich in EPA and DHA have been used in several human trials of patients with ARDS.…”

The pathophysiology of SARS-CoV-2: A suggested model and therapeutic approach

“…Inflammasome activation is also dependent on the upregulation of NF-κB [ 297 , 299 ]. Importantly there is an accumulating body of evidence implicating elevated NF-κB in the pathogenesis and progression of ARDS [ [300] , [301] , [302] , [303] ].…”