Lipoxin biosynthesis. There are at least 3 different biosynthetic pathways for lipoxin generation. All lead to the insertion of molecular oxygen at 2 sites in arachidonic acid by a variety of different enzymes that are generally segregated in different cell types and subject to regulation by cytokines and other inflammatory stimuli. In the first pathway (A), LXA₄ is generated through the action of 15-LO from airway epithelia or myeloid cells (neutrophils, monocyte/macrophages), which is followed by the action of 5-LO in myeloid cells. In the second pathway (B), LXA₄ is generated from leukotriene A₄ (LTA₄) (itself a product of 5-LO activity, and a leukotriene precursor) through the action of 15-LO or platelet-derived 12-LO. In the third pathway (C), arachidonic acid is converted to aspirin-triggered lipoxins (ATLs) such as 15-epi-LXA₄, via the action of epithelial or endothelial COX-2 in the presence of aspirin, which is followed by the action of 5-LO. The ATLs have similar activities but greater functional potency due to their relative resistance to metabolic inactivation. These pathways likely operate both independently and in a coregulated fashion in different tissues and biological situations. H(p)ETE, hydroperoxyeicosatetraenoic acid; mono, monocyte/macrophage; PMN, polymorphonuclear neutrophil.