Lipoxin

  Lipoxins are a series of anti-inflammatory mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoids whose appearance in inflammation signals the resolution of inflammation. They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. At present two lipoxins have been identified; lipoxin A₄ (LXA₄) and lipoxin B₄ (LXB₄).

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History

Lipoxins were first described by Serhan, Hamberg and Samuelsson in 1984.^[1] They reported that the lipoxins stimulated superoxide anion (O₂⁻) generation and degranulation at submicromolar concentrations—as potent as LTB₄.

Biosynthesis

Lipoxins are derived enzymatically from arachidonic acid, an ω-6 fatty acid. An analogous class, the resolvins, is derived from EPA and DHA, ω-3 fatty acids.^[1] Another analogous class, the epi-lipoxins, is formed by non-enzymatic peroxidation.

Biological activity

Lipoxins, as well as certain peptides, are high affinity ligands for the lipoxin A₄ receptor (LXA4R), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the LXA4R inhibits chemotaxis, transmigration, superoxide generation and NF-κB activation.^[2]

Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization.^[2] The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase proteins, bacterial peptides, HIV envelope proteins and neurotoxic peptides.

Similarly to the leukotrienes, LXA₄ will form the cysteinyl-lipoxins LXC₄, LXD₄ and LXE₄.^[3] At subnanomolar concentrations, LXA₄ and LXB₄ inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.^[4]

Lipoxins are high affinity antagonists to the cysteinyl leukotriene receptor type 1 (CysLT1) to which several leukotrienes (LTC₄, LTD₄ and LTE₄) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug montelukast (Singulair®).^[5]

In resolution

During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis).^[6] During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4, which promote the resolution phase of inflammation.^[7]

Lipoxin analogues

Stable synthetic analogues of LXs and aspirin-triggered 15-epi-LXA₄s (ATLs) can mimic many of the desirable anti-inflammatory, "pro-resolution" actions of native LXs.^[8]

References