Lipoxin

Lipoxins (LXs or Lxs), an acronym for lipoxygenase interaction products, are bioactive autacoid metabolites of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs viz., the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4, respectively. Lipoxins (LXs or Lxs), an acronym for lipoxygenase interaction products, are bioactive autacoid metabolites of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs viz., the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4, respectively. LXA4 and LXB4 were first described by Serhan, Hamberg, and the Nobel laurate Samuelsson in 1984. They reported that human blood neutrophils, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LX's, mounted superoxide anion (O2−) generation and degranulation responses. Both responses are considered to be pro-inflammatory in that, while aimed at neutralizing invading pathogens and digesting foreign material, can contribute to damaging host tissues and thereby prolonging and promoting further inflammation. Subsequent studies, however, found that these lipoxins, as well as their epimers, epi-LXA4 and LXB4, act primarily to dampen and resolve inflammation, i.e. they are anti-inflammatory cell signaling agents. Lipoxins are derived enzymatically from arachidonic acid, an ω-6 fatty acid. Structurally, they are defined as arachidonic acid metabolites that contain three hydroxyl residues (also termed hydroxy residues) and four double bonds. This structural definition distinguishes them from other SPMs such as the resolvins, neuroprotectins, and maresins, which are metabolites of the omega 3 fatty acids, eicosapentaenoic acid or docosahexaenoic acid, as well as a range of metabolites derived from other PUFAs (see specialized pro-resolving mediators). All of these other SPMs have activities and functions similar, although not necessarily identical, to the lipoxins . Formation of LXs is conserved across a broad range of animal species from fish to humans. Biosynthesis of the LXs requires two separate enzymatic attacks on arachidonic acid (AA). One attack involves attachment of a hydroperoxy (-O-OH) residue to carbon 15, conversion of this species to a 14,15-epoxide, and the resolution of this epoxide to form either 14,15-dihydroxy-eicosatetraenoate or 15-hydroxy-eicosatetraenoate products. This step is catalyzed by enzymes with 15-lipoxygenase activity which in humans includes ALOX15, ALOX12, aspirin-treated cyclooxygenase 2, and cytochrome P450s of the microsomal, mitochondrial, or bacterial subclasses. ALOX15B may also conduct this metaboism. The other enzyme attack point forms a 5,6-epoxide which is resolved to either 5,6-dihydroxy-eicosatetraenoate or 5-hydroxy eicosatetraenoate products; this step catalyzed by 5-lipoxygenase (ALOX5). Accordingly, these double oxygenations yield either 5,6,15-trihydroxy- or 5,14,15-trihydroxy-eicosatetraenoates. The double oxygenations may be conducted within a single cell type which possess ALOX5 and an enzyme with 15-lipoxygenase activity or, alternatively, by two different cell types, each of which possesses one of these enzyme activities. In the latter transcellular biosynthetic pathway, one cell type forms either the 5,6-dihydroxy-, 5-hydroxy, 14,15-dihydroxy- or a 15-hydroxy-eicosatetraenoate, and then passes this intermediate to a second cell type, which metabolizes it to the final LX product. For example, LXs are formed by platelets which, lacking ALOX5, cannot synthesize them. Rather, neutrophils form, the 5,6-epoxide, leukotriene A4 (LTA4), via ALOX5 and passed it to platelets that then reduce it a 5,6-dihydroxy-eicosateteraenoate product and further metabolize it through ALOX12 to form the 15-hydroxy product, LXA4. The two LXs are distinguished form their 15-epi-LTX epimers by their structural formulae: Note that the two LXs have their 15-hydroxyl residues in the S chirality configuration because all of the ALOX enzymes form 15S-hydroxy AA products. In contrast, the 15-hydroxy residues of the two epi-LXs are 15R chirality products because they are synthesized by aspirin-treated cyclooxygenase 2 or the microsomal, mitochondrial, or bacterial Cytochrome P450s; these enzymes form almost entirely or partly 15R-hydroxy products. (15-Epi-LTA44 and 15-epi-LTB44 are sometimes termed AT-LxA4 and AT-LxB4, respectively, when acknowledging their formation by aspirin-treated cyclooxygenase 2, i.e. by Aspirin-Triggered cyclooxygenase 2.) In addition to the pathways cited above, other transcellular metabolic routes have been shown to make LXs. For example, 5-lipoxygenase (i.e. (ALOX5) in neutrophils and 15-lipoxygenase-1 (i.e. ALOX15) in immature erythrocytes and reticulocytes operate in series to form LxA44 and LxB44; this pathway also occurs in serial interactions between neutrophils and eosinophils; between epithelium or M2 Macrophages/monocytes and neutrophils; and endothelium or skeletal muscle and neutrophils. The lipoxins commonly form as a consequence of stimulating the production of pro-inflammatory arachidonic acid metabolites. However, certain cytokines such as IFN-γ and IL-1β further increase production of the lipoxins (as well as other anti-inflammatory PUFA metabolites and proteins, e.g. IL4. LXs are rapidly metabolized, mainly by macrophages, to inactive products by being oxidized at carbon 15 to form 15-keto (also termed 15-oxo) LX products by a 15-hydroxyprostaglandin dehydrogenase; 15-oxo-LXA4 may be further metabolized to 13,14-dihydro-LXA4 by an oxidoreductase. 15-Epi-LXA4 and 15-epi-LXB4 are more resistant to the dehydrogenation enzyme than their LX epimers. In consequence of the operation of this anabolic pathway, LXs have very short half-lives in vivo, the epi-LXs have longer in vivo half-lives and thereby greater potencies than their LX epimers, and synthetic lipoxins that are metabolically resistant to this pathway have been prepared, used in animal models to study LX activities, and tested as potential therapeutic agents in animals and humans. Similar to various other AA metabolites such as LTA4 and 5-oxo-eicosatetraenoic acid, cells and tissues may convert LXs to 20-hydroxy products by omega oxidation; they also have been shown to ligate LXA4 to glutathione to form cysteinyl-lipoxins, initially LXC4, which is then sequentially metabolized to LXD4 and LXE4. The role of these pathways in limiting or contributing to the activity of the LXs has not been fully evaluated.