Lipoxin A4

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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).

General Properties

*Molecular Weight

352.47

*Molecular Formula

C₂₀H₃₂O₅

*IUPAC NAME

(5S,6R,7E,9E,11Z,13E,15S)-5,6,15-trihydroxyicosa-7,9,11,13-tetraenoicacid

*Canonical Smiles

CCCCCC(C=CC=CC=CC=CC(C(CCCC(=O)O)O)O)O

*Isomeric Smiles

CCCCC[C@@H](C=CC=C/C=C/C=C/[C@H]([C@H](CCCC(=O)O)O)O)O

PhysioChemical Properties

*Melting Point

*LogP

*Water Solubility

History

Lipoxins were first described by Serhan, Hamberg and Samuelsson in 1984.<ref name=Serhan /> 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.<ref name=Serhan>Template:Cite web Original description of lipoxins.</ref> 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.<ref name=Chiang>Template:Cite web </ref>

Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization.<ref name=Chiang /> 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.<ref name="pmid7706749">Powell WS, Chung D, Gravel S (1995). "5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration". J. Immunol. 154 (8): 4123–32. PMID 7706749. </ref> At subnanomolar concentrations, LXA₄ and LXB₄ inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.<ref name="pmid8690917">Papayianni A, Serhan CN, Brady HR (1996). "Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells". J. Immunol. 156 (6): 2264–72. PMID 8690917. Retrieved on 2007-11-01.</cite> </ref>

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).<ref name=Drazen><cite style="font-style:normal">Drazen J., Israel E., and O'Byrne P. (1999). "Treatment of Asthma with Drugs Modifying the Leukotriene Pathway". PMID 9895400. Retrieved on 2006-04-28.</cite> </ref>

In resolution

During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis).<ref name="pmid12239238"><cite style="font-style:normal">Mitchell S, Thomas G, Harvey K, et al (2002). "Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo". J. Am. Soc. Nephrol. 13 (10): 2497–507. doi:10.1097/01.ASN.0000032417.73640.72. PMID 12239238.</cite> </ref> 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.<ref name=McMahon>Template:Cite web Invited review article.</ref>

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.<ref name="pmid11478982"><cite style="font-style:normal">McMahon B, Mitchell S, Brady HR (2001). "Lipoxins: revelations on resolution". Trends Pharmacol. Sci. 22 (8): 391–5. doi:10.1016/S0165-6147(00)01771-5. PMID 11478982.</cite> </ref>

References

External Links

• [1]Pubchem
• [2]KEGG Compound
• [3]Human Metabolome DataBase

Categories:Hormones