lipoxins

Lipoxin B₄
Names
	IUPAC name 5S,14R,15S-Trihydroxy-6E,8Z,10E,12E -eicosatetraenoic acid
	Other names LXB4
Identifiers
CAS Registry Number	92950-25-9
ChEBI	CHEBI:6499
ChemSpider	4444430
	InChI InChI=1S/C20H32O5/c1-2-3-8-14-18(22)19(23)15-10-7-5-4-6-9-12-17(21)13-11-16-20(24)25/h4-7,9-10,12,15,17-19,21-23H,2-3,8,11,13-14,16H2,1H3,(H,24,25)/b6-4-,7-5+,12-9+,15-10+/t17-,18+,19-/m1/s1 ; Key: UXVRTOKOJOMENI-WLPVFMORSA-N ; InChI=1/C20H32O5/c1-2-3-8-14-18(22)19(23)15-10-7-5-4-6-9-12-17(21)13-11-16-20(24)25/h4-7,9-10,12,15,17-19,21-23H,2-3,8,11,13-14,16H2,1H3,(H,24,25)/b6-4-,7-5+,12-9+,15-10+/t17-,18+,19-/m1/s1; Key: UXVRTOKOJOMENI-WLPVFMORBP ;
IUPHAR/BPS	5216
Jmol-3D images	Image
PubChem	5280915
	SMILES O=C(O)CCC[C@H](O)/C=C/C=C\C=C\C=C\[C@@H](O)[C@@H](O)CCCCC ;
Properties
Chemical formula	C20H32O5
Molar mass	352.46508 g/mol
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/17 23:09:35」(JST)

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Lipoxin A₄

Lipoxins are members of the family of bioactive products generated from Arachidonic Acid (AA). They have a number of immunomodulatory and anti-inflammatory actions. 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.^[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. One important precursor to the lipoxins is 15-hydroxyicosatetraenoic acid (i.e. 15(S)-HETE) and its 15-hydroperoxy precusor. Transcellular biosynthetic mechanisms play a key role in their production. They are formed by platelets but they alone cannot synthesize them. Platelets depend upon neutrophils for LTA₄, which is converted to LXA₄ and LXB₄ by the action of platelet 12-lipoxygenase. LTC₄, LTD_4, and LTE₄ are also synthesized in platelets from LTA₄. An analogous class, the resolvins, are derived from EPA and DHA, ω-3 fatty acids.^[1] 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 (ALX), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). At least 6 homologues of this promiscuous receptor are found in mice. 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.

At higher concentrations, LXA₄ has been shown to bind AhR, the arylhydrocarbon receptor, but only in murine cells.^[3] More recently, LXA₄ was demonstrated to bind Estrogen receptor alpha and to act as an estrogenic molecule in human endometrial epithelial cells in vitro and in mouse uterine tissue in vivo.^[4]

Similarly to the leukotrienes, LXA₄ will form the cysteinyl-lipoxins LXC₄, LXD₄ and LXE₄.^[5] At subnanomolar concentrations, LXA₄ and LXB₄ inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells.^[6] The receptor for LXB4 has not been identified.

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).^[7]

In resolution

During inflammation, cells die by apoptosis. As part of resolution, lipoxins signal macrophages to the remains of these cells (phagocytosis).^[8] 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.^[9]

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.^[10]

References

^ ^a ^b Charles N. Serhan, Mats Hamberg, and Bengt Samuelsson (September 1, 1984). "Lipoxins: Novel Series of Biologically Active Compounds Formed from Arachidonic Acid in Human Leukocytes" (PDF). Retrieved 2006-02-02. Original description of lipoxins.
^ ^a ^b Chiang N., Arita M., and Serhan CN. (2005). "Anti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX". Prostaglandins, Leukotrienes and Essential Fatty Acids 73 (3–4): 163–177. doi:10.1016/j.plefa.2005.05.003. PMID 16125378.
^ Biochemistry. 1999 Jun 8;38(23):7594-600.Lipoxin A4: a new class of ligand for the Ah receptor.Schaldach CM, Riby J, Bjeldanes LF. PMID 10360957
^ Lipoxin A4 is a novel estrogen receptor modulator.Russell R, Gori I, Pellegrini C, Kumar R, Achtari C, Canny GO.FASEB J. 2011 Dec;25(12):4326-37. doi: 10.1096/fj.11-187658. PMID 21885654
^ 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.
^ 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.
^ Drazen J., Israel E., and O'Byrne P. (N Engl J Med. 1999 January 21;340(3):197-206). "Treatment of Asthma with Drugs Modifying the Leukotriene Pathway". The New England Journal of Medicine 340 (3): 197–206. doi:10.1056/NEJM199901213400306. PMID 9895400. Check date values in: |date= (help) CS1 maint: Date and year (link)
^ 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.
^ McMahon, Blaithin and Godson, Catherine (Am J Physiol Renal Physiol 286: F189-F201, 2004). "Lipoxins: endogenous regulators of inflammation". Retrieved 2006-02-07. Check date values in: |date= (help) Invited review article.
^ 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.

External links

Lipoxins at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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English Journal

The role of pro-resolution lipid mediators in infectious disease.

Russell CD, Schwarze J.Author information MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.AbstractInflammation is an essential host defence against infection, but can be damaging when excessive. Resolution of inflammation is an active process, and the pro-resolution effects of lipoxins, resolvins and protectins have received significant interest. Here, we review emerging data on the role of these lipid mediators in infectious disease. Lipoxins influence host control of Mycobacterium tuberculosis, Toxoplasma gondii, Trypanosoma cruzi and Plasmodium berghei cerebral malaria in mice. Their effects are protective in toxoplasmosis, T. cruzi infection and cerebral malaria but detrimental in tuberculosis; related to the balance between pathogen-control and excessive immune response. Topical lipoxin abrogates the tissue damage seen in a rabbit model of Porphyromonas gingivalis periodontitis. The increased virulence of H5N1 influenza A virus in mice correlates with reduced expression of SOCS2, required to mediate the effects of lipoxin. Mice unable to synthesize lipoxin suffer increased lung pathology during respiratory syncytial virus infection. Protectin suppresses influenza A virus replication in vitro and increases survival in a mouse model of severe influenza infection. Resolvins were investigated in a number of animal models of systemic bacterial infection, and were found to enhance phagocytic clearance of bacteria, reduce inflammation severity, promote neutrophil apoptosis, modulate neutrophil chemotaxis and importantly, reduce mortality. Interestingly, resolvin also enhances the antibacterial effect of ciprofloxacin and vancomycin. Topical resolvin application reduces the severity of herpes simplex virus ocular infection in mice. If the effects of these mediators translate from pre-clinical studies into successful clinical trials, they represent promising new strategies in managing infectious disease.
Immunology.Immunology.2014 Feb;141(2):166-73. doi: 10.1111/imm.12206.
Inflammation is an essential host defence against infection, but can be damaging when excessive. Resolution of inflammation is an active process, and the pro-resolution effects of lipoxins, resolvins and protectins have received significant interest. Here, we review emerging data on the role of thes
PMID 24400794

Lipid antigens in immunity.

Dowds CM, Kornell SC, Blumberg RS, Zeissig S.AbstractLipids are not only a central part of human metabolism but also play diverse and critical roles in the immune system. As such, they can act as ligands of lipid-activated nuclear receptors, control inflammatory signaling through bioactive lipids such as prostaglandins, leukotrienes, lipoxins, resolvins, and protectins, and modulate immunity as intracellular phospholipid- or sphingolipid-derived signaling mediators. In addition, lipids can serve as antigens and regulate immunity through the activation of lipid-reactive T cells, which is the topic of this review. We will provide an overview of the mechanisms of lipid antigen presentation, the biology of lipid-reactive T cells, and their contribution to immunity.
Biological chemistry.Biol Chem.2014 Jan 1;395(1):61-81. doi: 10.1515/hsz-2013-0220.
Lipids are not only a central part of human metabolism but also play diverse and critical roles in the immune system. As such, they can act as ligands of lipid-activated nuclear receptors, control inflammatory signaling through bioactive lipids such as prostaglandins, leukotrienes, lipoxins, resolvi
PMID 23999493

Japanese Journal

炎症収束因子—自然免疫から獲得免疫への橋梁—

遠藤平仁
日本臨床免疫学会会誌 36(3), 156-161, 2013
体外からの細菌感染や外傷などによる急性炎症は早期に血管浸過性亢進と好中球を中心とする炎症細胞の浸潤が起こる．炎症により破壊された組織は正常の組織に修復される．急性炎症で好中球の浸潤がおこりその後マクロファージ，リンパ球の浸潤と異物の貪食除去の炎症収束，組織修復と生体反応は展開する．急性炎症は自己制御され収束（Resolution）し組織修復する．この転換期に脂質メデイエータのLipoxinやR …
NAID 130003364173

Oxymetazoline Inhibits and Resolves Inflammatory Reactions in Human Neutrophils

, , [他], ,
Journal of pharmacological sciences 110(3), 276-284, 2009-07-20
… In a follow up study, we hypothesized that OMZ generates pro-resolving lipoxins being paralleled by production of immune-modulating prostaglandin E2 (PGE2) and anti-inflammatory 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] and depletion of pro-inflammatory leukotriene B4 (LTB4). …
NAID 10025737513

Related Pictures

Inhibitory action of Lipoxin A4 on PDGF Inhibitory action of Lipoxins and Resolvin Síntesis de la lipoxins de , lipoxins and 15-epimeric-lipoxins of the aspirin-triggered lipoxins Synthesis of the lipoxins from arachidonic Role of Lipoxins in Anti-inflammatory