Protective Actions of Aspirin-Triggered (17R) Resolvin D1 and Its Analogue, 17R-Hydroxy-19-Para-Fluorophenoxy-Resolvin D1 Methyl Ester, in C5a-Dependent IgG Immune Complex–Induced Inflammation and Lung Injury

Abstract

Increasing evidence suggests that the novel anti-inflammatory and pro-resolving mediators such as the resolvins play an important role during inflammation. However, the functions of these lipid mediators in immune complex (IC)-induced lung injury remain unknown. Here, we determined the role of aspirin-triggered resolvin D1 (AT-RvD1) and its metabolically stable analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester (p-RvD1), in IgG IC-induced inflammatory responses in myeloid cells and injury in the lung. We show that lung vascular permeability in the AT-RvD1- or p-RvD1-treated mice were significantly reduced when compared with values in mice receiving control vesicle during the injury. Furthermore, i.v. administration of either AT-RvD1 or p-RvD1 caused significant decreases in the bronchoalveolar lavage fluids (BALF) contents of neutrophils, inflammatory cytokines, and chemokines. Of interest, AT-RvD1 or p-RvD1 significantly reduced BALF complement C5a level. By Electrophoretic Mobility Shift Assay, we demonstrate that IgG IC-induced activation of NF-κB and C/EBPβ transcription factors in the lung were significantly inhibited by AT-RvD1 and p-RvD1. Moreover, AT-RvD1 dramatically mitigates IgG IC-induced NF-κB and C/EBP activity in alveolar macrophages. Also, secretion of TNF-α, IL-6, KC, and MIP-1α from IgG IC-stimulated alveolar macrophages or neutrophils was significantly decreased by AT-RvD1. These results suggest a new approach to the blocking of IC-induced inflammation.

Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis

“…9). RvD1 is one of the candidates that has been reported previously for treating a number of inflammatory diseases (34,35,(37)(38)(39)70). Here, we found it to be significantly effective in attenuating clinical symptoms in the preclinical mouse model of MS.…”

“…We decided to use RvD1, a downstream metabolite of EPA-DHA, to examine its therapeutic potential in the EAE model. RvD1 has been proven to be very potent in treating a number of inflammation-associated human diseases, including peritonitis (34), dextran sulfate sodium-induced colitis (35), sepsis (36), adjuvant-induced arthritis (37), asthma (38), and immune complex-induced inflammation (39). There are no reports examining the effect of RvD1 in EAE disease progression.…”

Resolvin D1 activates the inflammation resolving response at splenic and ventricular site following myocardial infarction leading to improved ventricular function

“…17R-HDHA is then converted by 5-LOX to create AT-RvD1 [3]. The pro-resolving role of RvD1 has been studied [11] in a number of systems including metabolic disease and infections [12, 13]. The rapid conversion of RvD1 by eicosanoid oxidoreductase to 8-oxo- and 17-oxo-RvD1 dramatically lowers its bioactivity [14].…”

Implications for eicosapentaenoic acid- and docosahexaenoic acid-derived resolvins as therapeutics for arthritis

“…We have shown that RvD1 treatment in a model of peritonitis in vivo significantly reduces the levels of a number of pro-inflammatory mediators after zymozan administration, including prostaglandins and leukotriene B 4 (Norling et al, 2012). In addition, AT-RvD1 dramatically mitigates immunoglobulin G immune complex-induced nuclear factor-κB and CCAAT/enhancer binding protein activity in alveolar macrophages, and secretion of tumor necrosis factor-α, interleukin-6, and macrophage inflammatory protein 1α from immunoglobulin G immune complex-stimulated alveolar macrophages or neutrophils (Tang et al, 2014). RvD2 treatment also alters the cytokine and eicosanoid profiles, reducing interleukin-17, interleukin-10, prostaglandin E 2 and leukotriene B 4 in a murine polymicrobial sepsis model .…”

“…The formation of immunoglobulin G immune complexes in lung also results in in situ generation of the complement activation product complement 5a, resulting in the recruitment of inflammatory cells (Gao et al, 2006;Guo and Ward, 2002). In a recent study, AT-RvD1 was shown to have the ability to regulate the Fc-γ receptor-mediated induction of inflammatory cytokines and chemokines in both macrophages and neutrophils, and also reduced complement 5a levels in the bronchoalveolar lavage fluid in an immunoglobulin G immune complex-induced lung injury model (Tang et al, 2014).…”