Figure 4.

Categorization of inflammation- and resolution-promoting agents. In response to pathogens or injury stimuli (PAMPs, DAMPs), phospholipase A2 (PLA2)-induced biosynthesis of arachidonic acid (AA) leads to the production of proinflammatory lipid mediators including thromboxanes, leukotrienes, and prostaglandins. Such events mark the initiation phase of acute inflammation characterized by PMN chemotaxis, pro-inflammatory-[M1]-macrophages recruitment, and enhanced proinflammatory signals (NLRP3 inflammasome, NF-κB, IL-1β, CXCL1/2). Phagocytic M1-macrophages release 12/15 LOX, which promotes the activation of lipid-mediators (LM) class switching, where AA, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) interact with 12LOX and 15LOX enzymes to be metabolized into specialized pro-resolving mediators (SPMs) including PGD2 from AA, D-series resolvins from DHA, or E-series resolvins from EPA. SPMs promote anti-inflammatory (M2)-macrophage recruitment, inhibition of proinflammatory cytokines’ secretion, termination of inflammation, and regeneration of optimal functions. When the resolution mechanisms fail to occur, inflammation is perpetuated. Inflammatory mediators are overexpressed, leading to persistence of cellular damages, necrosis, fibrosis, loss of function and cardiac vulnerability to arrhythmias, and heart failure. Strategies promoting the augmentation of pro-resolution mechanisms can potentially limit, or eventually reverse, some chronic-inflammation-induced cardiac disorders.