Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

Abstract

Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.

Summary of Proceedings and Expert Consensus Statements From the International Summit “Lipids in Parenteral Nutrition”

“…SPMs include resolvins, protectins, and maresins . Synthesized directly from the ω‐3 fatty acids DHA and EPA, SPMs initiate signaling cascades that activate pathways involved in the resolution of inflammation . Specifically, SPMs promote cessation of leukocyte infiltration, stimulate macrophage uptake of apoptotic cells, and facilitate clearance of cellular debris .…”

Lipid Use in Hospitalized Adults Requiring Parenteral Nutrition

“…These include a closer attention to glycemic control and a broader availability of lipid emulsions in recent years, particularly mixes of lipids containing soybean oil, olive oil, MCT, and fish oil. In addition, we realize that fish oil has anti‐inflammatory and immunomodulatory effects, and it contains docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), now known to be direct precursors of endogenously produced specialized pro‐resolution mediators (ie, resolvins, protectins, and maresins) that improve outcomes in many animal disease models . Moreover, the resolvins and protectins can promote better macrophage and neutrophil killing without increasing the inflammatory response, which may be of particular benefit in some groups such as those with hyperdynamic septic shock.…”

“…While all commercially available lipid emulsions suffice as an energy supply and contain enough essential fatty acids to prevent EFAD, those containing only soybean oil as a lipid source have a high ω‐6:ω‐3 fatty‐acid ratio and abundance of phytosterols, raising concerns about their inflammatory and hepatotoxic potential in some patients . Conversely, there is a growing body of evidence that ω‐3 fatty acids can exert beneficial immunomodulatory, anti‐inflammatory, and resolution of inflammation effects across a wide range of patient groups including surgical, cancer, and critically ill patients . In addition, lipid emulsions based on fish oil contain high levels of the antioxidant vitamin E, which may help to reduce oxidative stress during inflammatory conditions.…”

Immuno‐Resolving Ability of Resolvins, Protectins, and Maresins Derived from Omega‐3 Fatty Acids in Metabolic Syndrome

“…E‐series resolvins include resolvin E1 (RvE1) and resolvin E2 (RvE2) ( Figure 1A). The complete structure of RvE1 is 5 S ,12 R ,18 R ‐trihydroxy‐6 Z ,8 E ,10 E ,14 Z ,16 E ‐eicosapentaenoic acid, while that of RvE2 is 5 S ,18 R ‐dihydroxy‐6 E ,8 Z ,11 Z ,14 Z ,16 E ‐eicosapentaenoic acid . The first step in the biosynthesis of E‐series resolvins is the oxygenation of EPA, resulting in 18 R ‐hydroperoxy‐eicosapentaenoic acid (18 R ‐HpEPE) (Figure 1B).…”

“…This step is catalyzed by acetylated cyclooxygenase‐2 (COX‐2), which is formed in the presence of aspirin . The oxygenated EPA (18 R ‐HpEPE) is quickly reduced to 18 R ‐hydroxy‐eicosapentaenoic acid (18 R ‐HEPE) and the product is subjected to a second oxygenation by 5‐lipoxygenase (5‐LOX), resulting in the formation of hydroperoxide . This hydroperoxide intermediate is converted into an epoxide that undergoes enzymatic hydrolysis through a hydrolase to produce RvE1.…”