Lipoxins (LXs)
Lipoxin A4 (LXA4; 5S, 6R, 15S-trihydroxy-7E, 9E, 11Z, 13E-eicosatetraenoic acid) and lipoxin B4 (LXB4; 5S, 14R, 15S-trihydroxy-6E, 8Z, 10E, 12E-eicosatetraenoic acid) were the first lipid SPMs to be discovered (Chiang and Serhan 2017). They are produced from the conversion of omega-6 (ω-6) arachidonic acid (AA) by lipoxygenase (LOX) through unicellular and transcellular biosynthesis pathways. In transcellular biosynthesis, LXs are synthesized by12-LOX derived through platelet-leukocyte interaction while unicellular biosynthesis pathways involve a series of LOXs-15-lipoxygenase, 5-lipoxygenase, and epoxide hydrolase reactions. In addition to the lipoxygenase-initiated biosynthesis, two distinct lipoxins biosynthesis pathways have been elucidated; aspirin-triggered and statin-triggered routes. Aspirin induces the production of a lipoxin named “aspirin-triggered " (AT) 15-epi-LX through acetylation of serine residue of cyclooxygenase-2 (COX-2), acetylated COX-2 transforms AA into 15R-HETE, which serves as a substrate for 5-LOX (Chiang et al. 2005). Statins, widely used as potent cholesterol-lowering agents, have also been found to enhance the conversion of arachidonate to 15-epi-LX (Planaguma et al. 2010). Epi-lipoxins, trihydroxy metabolites of arachidonic acid, are 15R-epimers of their respective lipoxins, 15-epi-LXA4, LXA4, and 15-epi-LXB4, LXB4 (Romano et al. 2015).
In vivo biosynthesis of LXA4 is triggered in an acute inflammatory process in which Polymorphonuclear neutrophil (PMN)’s interaction with PGE2 and PGD2 activates 15-lipoxygenase subsequently facilitating LXA4 biosynthesis (Claria and Serhan 1995). In a murine peritonitis model, the maximum level of LXA4 was achieved within 2 hours and gradually decreased during the first 24 hours (Bannenberg et al. 2005). The formation of LXs is preserved across a wide range of animal species, from fish to humans (Levy 2005). This indicates the physiological importance of LXs.