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).

History
Lipoxins were first described by Serhan, Hamberg and Samuelsson in 1984. They reported that the lipoxins stimulated superoxide anion (O2&minus;) generation and degranulation at submicromolar concentrations&mdash;as potent as LTB4.

Biosynthesis
Lipoxins are derived enzymatically from arachidonic acid, an &omega;-6 fatty acid. An analogous class, the resolvins, are derived from EPA and DHA, &omega;-3 fatty acids. Another analogous class, the epi-lipoxins, are 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.

Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization. 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. At subnanomolar concentrations, LXA4 and LXB4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.

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).

In resolution
During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis). During the acute inflammatory process, the proinflammatory cytokines such as IFN-&gamma; and IL-1&beta; can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4, which promote the resolution phase of inflammation.

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.