Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins

Abstract

The resolution of acute inflammation is a process that allows for inflamed tissues to return to homeostasis. Resolution was held to be a passive process, a concept now overturned with new evidence demonstrating that resolution is actively orchestrated by distinct cellular events and endogenous chemical mediators. Among these, lipid mediators, such as the lipoxins, resolvins, protectins, and newly identified maresins, have emerged as a novel genus of potent and stereoselective players that counter-regulate excessive acute inflammation and stimulate molecular and cellular events that define resolution. Given that uncontrolled, chronic inflammation is associated with many cardiovascular pathologies, an appreciation of the endogenous pathways and mediators that control timely resolution can open new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation, as well as correcting the impact of chronic inflammation in cardiovascular disorders. Here, we overview and update the biosynthesis and actions of proresolving lipid mediators, highlighting their diverse protective roles relevant to vascular systems and their relation to aspirin and statin therapies.

Figure 1. Key cellular actions of lipoxins and resolvins

Lipoxin A₄ is generated from arachidonic acid (AA), while omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), serve as precursors for E-series and D-series resolvins, respectively. Lipoxins and resolvins act in a stereospecific manner on distinct cell types through interaction with G-protein coupled receptors (GPCRs) to stimulate non-phlogistic macrophage phagocytosis, increase anti-inflammatory cytokines and decrease pro-inflammatory cytokine generation in macrophages, neutrophils (PMN), endothelial cells and dendritic cells. Lipoxins and resolvins also stimulate endothelial production of nitric oxide (NO) and vasoprotective prostacyclin (PGI₂).

Figure 2. Biosynthetic scheme of D-series resolvins

Docosahexaenoic acid (DHA) is enzymatically converted to 17-hydroperoxydocosahexaenoic acid by 15-lipoxygenase (LOX). The 17-hydroperoxy intermediate is further transformed by 5-LOX via transcellular biosynthesis to form a 7,8-epoxide intermediate, which is enzymatically hydrolyzed to either resolvin D1 (RvD1) or RvD2. In the presence of aspirin, acetylated COX-2 converts DHA into 17-hydroxydocosahexaenoic acid in which the hydroxyl group is in the R configuration, rather than the S configuration. This intermediate is further transformed into aspirin-triggered RvD1 and RvD2.

Figure 3. Aspirin and statins promote the formation of 15-epi lipoxin A₄

Both aspirin and statins promote the generation of 15R-hydroxyeicosatetraenoic acid (HETE) from arachidonic acid via the acetylation or S-nitrosylation of COX-2, respectively. Through transcellular biosynthesis, 15R-HETE is further converted to 15-epi lipoxin A₄ by 5-lipoxygenase (LOX).

Figure 4. Novel anti-inflammatory and pro-resolving actions of lipoxins, resolvins and protectins in the vasculature

Tissue injury and microbial invasion precipitates the release of endogenous chemical mediators that increase vascular permeability and promote leukocyte chemotaxis in post-capillary venules, which characterizes the initiation of the acute inflammatory response. After killing the invading microbes, PMN undergo apoptosis and must be cleared by macrophages to allow for tissue homeostasis to be restored. During the time course of the acute inflammatory response, endogenous lipid mediators, such as the lipoxins (LX), resolvins (Rv) and protectins are generated and act locally to stop further vascular permeability and leukocyte chemotaxis, and promote the formation of anti-adhesive and anti-thrombotic mediators, NO and prostacyclin (PGI₂). These novel lipid mediators also stimulate phagocytosis and clearance of apoptotic PMN and microbes. Ungoverned activation of leukocytes and endothelial cells can lead to extracellular release of reactive oxygen species (ROS) and excessive leukocyte recruitment and/or altered clearance, which are prominent characteristics of chronic inflammatory diseases. (Illustration Credit: Cosmocyte/Cameron Slayden)