PMC:7534795 / 76027-82164 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7534795","sourcedb":"PMC","sourceid":"7534795","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7534795","text":"8.1.3 Anti-inflammatory features of the n-3 PUFAs-derived specialized pro-resolving mediators (SPMs)\nMetabolism of n-3 PUFAs also generates another group of highly specialized pro-resolving mediators (SPMs) which include resolvins ‘resolution phase interaction products’ produced from both EPA (E-series, RvE1-2) and DHA (D-series, RvD1-6) as well as protectins and maresins produced from DHA (Serhan et al., 2002; Serhan, Chiang, \u0026 Van Dyke, 2008). Both the COX and LOX pathways are involved in the synthesis of these metabolites with distinct epimers being produced in the presence and absence of aspirin (Mas, Croft, Zahra, Barden, \u0026 Mori, 2012).\nSPMs possess potent anti-inflammatory and inflammation resolving properties which is essential to terminate ongoing inflammatory processes, accelerate the cleaning process and aid in tissue regeneration and wound healing allowing tissue homeostasis to return (Serhan et al., 2000; Serhan et al., 2002; Spite et al., 2009; Titos et al., 2011). Several mechanistic pathways contribute to the anti-inflammatory effects of resolvins, protectins and maresins. This includes preventing the migration of neutrophils and monocytes across epithelial cells and promoting clearance of polymorphonuclear (PMNs) leukocytes, apoptotic cells and debris from the site of inflammation (Campbell et al., 2007; Serhan et al., 2002). Krishnamoorthy et al. showed resolvins inhibit tissue migration of neutrophils by lowering the expression of surface adhesion receptors on neutrophils, such as CD11b or CD18, and reducing the production of the chemokine IL-8 (Krishnamoorthy et al., 2010). Additionally, the partial agonist/antagonist activity of RvE1 toward LTB4 receptors on PMNs will inhibit NF-κB activation, abolish pro-inflammatory cytokine production and reduce PMN leukocyte infiltration (Arita et al., 2007; Serhan et al., 2002; Serhan et al., 2008). Resolvins can blunt reactive oxygen species (ROS) production from neutrophils, induce neutrophil apoptosis and clearance by macrophages, as well contribute to inhibiting chemokine signaling (Ariel et al., 2006; Schwab, Chiang, Arita, \u0026 Serhan, 2007; Serhan \u0026 Chiang, 2004). Furthermore, Morin et al. demonstrated a diet enriched with DHA and monoglycerides can significantly increase the levels of RvD2 and RvD3, which correlate with reduced levels of proinflammatory mediators CRP, IL-6, TNF-α, and IL-1β in a rat model of hypertension (Morin, Rousseau, Blier, \u0026 Fortin, 2015). Additionally, there is growing evidence for a role of SPMs in regulating the humoral immune response. A study conducted by Ramon et al., showed 17-hydroxydocosahexaenoic acid (17-HDHA), the precursor of the D-series SPMs (RvD1, 17R-RvD1, RvD2), can reduce IL-6 secretion in human B cells, increase B cell antibody production and promote B cell differentiation to an antibody secreting cell (Ramon, Gao, Serhan, \u0026 Phipps, 2012). These new findings highlight the potential applications of SPMs as non-toxic, supportive adjuvants and as anti-inflammatory therapeutic molecules particularly during infection as in the case of COVID-19.\nResolvins, protectins and maresins play a pivotal role regulating the function of macrophages. Sulciner et al. demonstrates RvD1, RvD2 or RvE1 can inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumors. These resolvins suppressed the release of the proinflammatory cytokines/chemokines, including TNFα, IL-6, IL-8, chemokine ligand 4, and chemokine ligand 5, by human macrophages cocultured with tumor cell debris (Sulciner et al., 2018). Maresins are conjugates of sulfides synthetized by macrophages, which are also participants in acute inflammation resolution and seem to promote tissue regeneration (Serhan et al., 2009). Maresin-1 biosynthesis involves an active intermediate (13S,14S-epoxi-DHA) that stimulates macrophage conversion from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype (Dalli, Ramon, Norris, Colas, \u0026 Serhan, 2015). It is noteworthy that M2 macrophages secrete resolvins, protectins and maresins to dampen inflammation and restore homeostasis (Bouchery \u0026 Harris, 2017; Ramon et al., 2016) and at the same time augment phagocytic capacity of macrophages and other cells to remove debris from the site(s) of infection and injury and enhance microbial clearance (Dalli et al., 2013; Norris et al., 2018; Poorani, Bhatt, Dwarakanath, \u0026 Das, 2016).\nThe role of resolvins in the resolution of inflammation has been demonstrated in several animal models of ALI and ARDS (Gao et al., 2017; Uddin \u0026 Levy, 2011; Wang, Yan, Hao, \u0026 Jin, 2018; Zhang et al., 2019). These studies carried out using rat and mouse models infected with the E.coli endotoxin, LPS, suggested the pro-resolving effects of these molecules could be attributed, for example, to the suppression of neutrophil infiltration due to reduced expression and release of pro-inflammatory cytokines from alveolar macrophages (Uddin \u0026 Levy, 2011; Zhang et al., 2019). Further, it has been demonstrated protectins may reduce the replication of influenza (Morita et al., 2013) and potentially affect the inflammatory manifestations of respiratory viral diseases (Russell \u0026 Schwarze, 2014).\nImportantly, pro-inflammatory cytokines, TNF-α and IL-6, will inhibit the activities of desaturases, which are essential for the generation of AA, EPA and DHA from their precursors LA and ALA (Das, 2013). Hence, in instances where there is a substantial degree of inflammation due to high levels of IL-6 and TNF-α, such as following COVID-19 infection, a deficiency of EPA and DHA and subsequent decreased generation of resolvins, protectins and maresins can occur (Das, 2018). Thus, administration of PUFAs and/or their metabolites, resolvins, protectins and maresins can suppress inappropriate production of IL-6 and TNF-α to resolve inflammation, enhance recovery and limit cytokine storm (Das, 2019) in COVID-19. Together, the studies imply administration of n-3 PUFA may enhance recovery from infections and further, if present in adequate amounts, may modulate the response to 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