*3.2. SPMs: Resolution Function*

The mechanisms involved in acute inflammatory conditions are critical for the restoration of tissue homeostasis [19,20]. The acute inflammatory response can be divided into two general phases: initiation of acute inflammation and resolution [23]. Initiation is marked by tissue edema, resulting from increased blood flow and vessel dilation that allows for the migration of leukocytes from the post-capillary lumen to the interstitial space [17,18]. This process is mediated by proinflammatory lipid mediators—namely, leukotrienes (LTs) and prostaglandins (PGs)—derived from the omega-6 fatty acid AA [28,67]. The initial recruitment of neutrophils (polymorphonuclear leukocytes (PMNs)) is followed by the recruitment of monocytes/macrophages from the blood and into the affected tissue [67,68]. In contained inflammatory exudates, coordinated lipid mediator class switching occurs in the course of acute inflammation and resolution (Figure 2) [23,69,70]. AA-derived LXA4 is the first PUFA-derived mediator found to have anti-inflammatory and pro-resolving activities [71,72]. Platelet-leukocyte interaction leads to the formation of LXA4 and LXB4, which stimulates the lipid signaling class switch by blocking the further recruitment of polymorphonuclear cells from post-capillary venules [73]. Once the noxious materials are removed via phagocytosis, the inflammatory reaction must be resolved to maintain homeostasis [70,74]. The resolution of acute inflammation is an active process that is controlled by SPMs [39,75]. These SPMs lead to the recovery of homeostasis by blocking leukocyte trafficking to the inflamed site, reversing vasodilation and vascular permeability, and promoting the clearance of inflammatory cells, exudates, and tissue debris [76,77]. In the lipid class-switch process, SPMs share similar biological functions, limiting neutrophil infiltration, shifting cytokine profiles from pro- to anti-inflammatory, and promoting macrophage phagocytosis [78].

**Figure 2.** The outcome of acute inflammation and resolution. Under stimulation of injury or infection, release of proinflammatory lipids (prostaglandin (PG), leukotriene (LT)), chemokines (C-C motif chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8)), and cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-6) induce the recruitment of neutrophils. Other immune cells (macrophages, B cells, and T cells) also participate in the process. Macrophages directly phagocytize organisms and apoptotic neutrophils, while B cells are converted into plasma cells to kill organisms through secreted antibodies, referred to as antibody-dependent cell-mediated cytotoxicity. Macrophages and B cells activate T cells via antigen cross presentation (AP). PGE2 leads to vasodilation and LTB4 stimulates PMN influx into the inflammatory locus. Subsequently, lipid mediator (LM) class switching converts proinflammatory signals into pro-resolving signals and triggers resolution. SPMs restrict excessive PMN influx to the injury site, enhance efferocytosis, and stimulate pro-resolving signals.
