A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediator (SPM) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during an inflammatory response and act to resolve it. The first lipoxins identified were lipoxin A4 (LXA4) and lipoxin B4 (LXB4), followed by their respective epimers, the epi-lipoxins 15-epi-LXA4 and 15-epi-LXB4.
History LXA4 and LXB4 were first described by Charles Serhan, Mats Hamberg, and Bengt Samuelsson in 1984. They reported that human blood neutrophils, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, 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.
Biochemistry 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 specialized pro-resolving mediators (SPMs), such as the resolvins, neuroprotectins, and maresins. All of these SPMs have activities and functions similar, although not necessarily identical, to the lipoxins.
Synthesis 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 metabolism. 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 possesses 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 pass it to platelets that then reduce it to a 5,6-dihydroxy-eicosateteraenoate product and further metabolize it through ALOX12 to form the 15-hydroxy product, LXA4. The two LXs are distinguished from their 15-epi-LTX epimers by their structural formulae:
LxA4: 5S,6R,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid LxB4: 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid 15-epi-LxA4: 5S,6R,15R-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid 15-epi-LxB4: 5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid 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-LxA4 and 15-epi-LxB4 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 LxA4 and LxB4; 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.
Stimulation of synthesis 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).
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