Editing Lipoxin

{{short description|Acronym for lipoxygenase interaction product}}
<!-- The structure diagram should highlight the chiral centers, as the epi-lipoxins differ only in chirality-->
{{Chembox
| verifiedrevid = 444255012
| Name = Lipoxins A<sub>4</sub> and B<sub>4</sub>
|  ImageFile = Lipoxin A4.svg
|  ImageSize = 200px
|  ImageCaption = Lipoxin A<sub>4</sub>
|  ImageFile1 = Lipoxin B4.svg
|  ImageCaption1 = Lipoxin B<sub>4</sub>
|  PIN=A4: (5''S'',6''R'',7''E'',9''E'',11''Z'',13''E'',15''S'')-5,6,15-Trihydroxyicosa-7,9,11,13-tetraenoic acid<br />B4: (5''S'',6''E'',8''Z'',10''E'',12''E'',14''R'',15''S'')-5,14,15-Trihydroxyicosa-6,8,10,12-tetraenoic acid
|  OtherNames = LXA4 and LXB4
|Section1= {{Chembox Identifiers
| IUPHAR_ligand = 1034
| IUPHAR_ligand_Comment = A4
| IUPHAR_ligand1 = 5216
| IUPHAR_ligand1_Comment = B4
| ChemSpiderID = 4444429
| ChemSpiderID_Comment = A4
| ChemSpiderID_Ref = {{chemspidercite|correct|}}
| ChemSpiderID1 = 4444430
| ChemSpiderID1_Comment = B4
| ChemSpiderID1_Ref = {{chemspidercite|correct|}}
| InChI_Comment = A4
| InChI = 1S/C20H32O5/c1-2-3-8-12-17(21)13-9-6-4-5-7-10-14-18(22)19(23)15-11-16-20(24)25/h4-7,9-10,13-14,17-19,21-23H,2-3,8,11-12,15-16H2,1H3,(H,24,25)/b6-4-,7-5+,13-9+,14-10+/t17-,18+,19-/m0/s1
| InChIKey = IXAQOQZEOGMIQS-SSQFXEBMSA-N
| InChI1_Comment = B4
| InChI1 = 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
| InChIKey1 = UXVRTOKOJOMENI-WLPVFMORSA-N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UXVRTOKOJOMENI-WLPVFMORSA-N
| CASNo_Comment = A4
| CASNo_Ref = {{cascite|correct}}
| CASNo = 89663-86-5
| CASNo1_Comment = B4
| CASNo1_Ref = {{cascite|correct}}
| CASNo1 = 98049-69-5
| PubChem_Comment = A4
| PubChem = 5280914
| PubChem1_Comment = B4
| PubChem1 = 5280915
| ChEBI = 6498
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI1 = 6499
| ChEBI1_Ref = {{ebicite|correct|EBI}}
| SMILES_Comment = A4
| SMILES = CCCCC[C@H](O)C=C\C=C/C=CC=CC(O)C(O)CCCC(O)=O
| SMILES1_Comment = B4
| SMILES1 = O=C(O)CCC[C@H](O)/C=C/C=C\C=C\C=C\[C@@H](O)[C@@H](O)CCCCC
}}
|Section2= {{Chembox Properties
|  Formula=C<sub>20</sub>H<sub>32</sub>O<sub>5</sub>
|  MolarMass=352.46508 g/mol
  }}
}}
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 eicosanoid]]s 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 A<sub>4</sub> (LXA<sub>4</sub>) and lipoxin B<sub>4</sub> (LXB<sub>4</sub>), followed by their respective [[epimer]]s, the [[epi-lipoxin]]s 15-epi-LXA<sub>4</sub> and 15-epi-LXB<sub>4</sub>.

==History==
LXA<sub>4</sub> and LXB<sub>4</sub> were first described by [[Charles N. Serhan|Charles Serhan]], Mats Hamberg, and [[Bengt I. Samuelsson|Bengt Samuelsson]] in 1984.<ref name="pmid6422933">{{cite journal | vauthors = Serhan CN, Hamberg M, Samuelsson B | title = Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes | journal = Biochemical and Biophysical Research Communications | volume = 118 | issue = 3 | pages = 943–9 | year = 1984 | pmid = 6422933 | doi = 10.1016/0006-291x(84)91486-4}}</ref>  They reported that human blood [[neutrophil]]s, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, mounted [[superoxide]] anion (O<sub>2</sub><sup>&minus;</sup>) 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-LXA<sub>4</sub> and LXB<sub>4</sub>, 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 [[Hydroxy group|hydroxyl]] residues (also termed hydroxy residues) and four [[double bond]]s. This structural definition distinguishes them from other [[specialized pro-resolving mediators]] (SPMs), such as the [[resolvin]]s, [[neuroprotectin]]s, and [[maresin]]s. All of these SPMs have activities and functions similar, although not necessarily identical, to the lipoxins.<ref name="pmid25052386">{{cite journal | vauthors = Qu Q, Xuan W, Fan GH | title = Roles of resolvins in the resolution of acute inflammation | journal = Cell Biology International | volume = 39 | issue = 1 | pages = 3–22 | year = 2015 | pmid = 25052386 | doi = 10.1002/cbin.10345 | s2cid = 10160642 }}</ref><ref name="pmid26546723">{{cite journal | vauthors = Weylandt KH | title = Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell | journal = European Journal of Pharmacology | volume = 785 | pages = 108–15 | year = 2016 | pmid = 26546723 | doi = 10.1016/j.ejphar.2015.11.002 }}</ref>

===Synthesis===
Formation of LXs is conserved across a broad range of animal species from fish to humans.<ref name="pmid16046112">{{cite journal | vauthors = Levy BD | title = Lipoxins and lipoxin analogs in asthma | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 73 | issue = 3–4 | pages = 231–7 | year = 2005 | pmid = 16046112 | doi = 10.1016/j.plefa.2005.05.010 }}</ref>  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 P450]]s 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.<ref name="pmid25895638">{{cite journal | vauthors = Romano M, Cianci E, Simiele F, Recchiuti A | title = Lipoxins and aspirin-triggered lipoxins in resolution of inflammation | journal = European Journal of Pharmacology | volume = 760 | pages = 49–63 | year = 2015 | pmid = 25895638 | doi = 10.1016/j.ejphar.2015.03.083 }}</ref><ref name="pmid26853678">{{cite journal | vauthors = Markworth JF, Maddipati KR, Cameron-Smith D | title = Emerging roles of pro-resolving lipid mediators in immunological and adaptive responses to exercise-induced muscle injury | journal = Exercise Immunology Review | volume = 22 | pages = 110–34 | year = 2016 | pmid = 26853678 }}</ref> 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.<ref name="pmid26457057">{{cite journal | vauthors = Chandrasekharan JA, Sharma-Walia N | title = Lipoxins: nature's way to resolve inflammation | journal = Journal of Inflammation Research | volume = 8 | pages = 181–92 | year = 2015 | pmid = 26457057 | pmc = 4598198 | doi = 10.2147/JIR.S90380 | doi-access = free }}</ref> For example, LXs are formed by platelets which, lacking ALOX5, cannot synthesize them. Rather, [[neutrophils]] form the 5,6-epoxide [[Leukotriene A4|leukotriene A<sub>4</sub>]] (LTA<sub>4</sub>) 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, LXA<sub>4</sub>.<ref name="pmid25895638"/> The two LXs are distinguished from their 15-epi-LTX epimers by their structural formulae:

*LxA<sub>4</sub>: 5''S'',6''R'',15''S''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid
*LxB<sub>4</sub>: 5''S'',14''R'',15''S''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid
*15-epi-LxA<sub>4</sub>: 5''S'',6''R'',15''R''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid    
*15-epi-LxB<sub>4</sub>: 5''S'',14''R'',15''R''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid
 
Note that the two LXs have their 15-hydroxyl residues in the ''S'' [[chirality]] configuration because all of the ALOX enzymes form 15''S''-hydroxy AA products. In contrast, the 15-hydroxy residues of the two epi-LXs are 15''R'' chirality products because they are synthesized by aspirin-treated cyclooxygenase 2 or the microsomal, mitochondrial, or bacterial [[cytochrome P450]]s; these enzymes form almost entirely or partly 15''R''-hydroxy products.<ref name="pmid25895638"/> (15-Epi-LxA<sub>4</sub> and 15-epi-LxB<sub>4</sub> are sometimes termed AT-LxA<sub>4</sub> and AT-LxB<sub>4</sub>, respectively, when acknowledging their formation by aspirin-treated cyclooxygenase 2, i.e. by '''A'''spirin-'''T'''riggered 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 LxA<sub>4</sub> and LxB<sub>4</sub>; this pathway also occurs in serial interactions between neutrophils and eosinophils; between [[epithelium]] or [[Macrophage#Subtypes|M2 macrophage]]s/monocytes and neutrophils; and [[endothelium]] or skeletal muscle and neutrophils.<ref name="pmid25895638"/><ref name="pmid26853678"/><ref name="pmid26457057"/>

===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 [[Interferon-gamma|IFN-γ]] and [[Interleukin 1|IL-1β]] further increase production of the lipoxins (as well as other anti-inflammatory PUFA metabolites and proteins, e.g. [[Interleukin 4|IL4]]).<ref name=McMahon>{{cite journal | url= http://ajprenal.physiology.org/cgi/content/full/286/2/F189 | title= Lipoxins: endogenous regulators of inflammation | author1= McMahon, Blaithin | author2= Godson, Catherine | journal= American Journal of Physiology. Renal Physiology | year= 2004 | volume= 286 | issue= 2 | pages= F189-201 | doi= 10.1152/ajprenal.00224.2003 | pmid= 14707005 | name-list-style= amp | accessdate= 2006-02-07 | archive-url= https://web.archive.org/web/20100125010453/http://ajprenal.physiology.org/cgi/content/full/286/2/F189 | archive-date= 2010-01-25 | url-status= dead | url-access= subscription }} Invited review article.</ref>

===Further metabolism===
LXs are rapidly metabolized, mainly by macrophages, to inactive products by being oxidized at carbon 15 to form 15-[[Ketone|keto]] (also termed 15-oxo) LX products by a [[15-hydroxyprostaglandin dehydrogenase]]; 15-oxo-LXA<sub>4</sub> may be further metabolized to 13,14-dihydro-LXA<sub>4</sub> by an [[oxidoreductase]]. 15-Epi-LXA<sub>4</sub> and 15-epi-LXB<sub>4</sub> are more resistant to the dehydrogenation enzyme than their LX epimers.<ref name="pmid16046112"/> In consequence of the operation of this [[anabolic]] pathway, LXs have very short half-lives ''in vivo''. The epi-LXs have longer ''in vivo'' half-lives and thereby greater potencies than their LX epimers, and synthetic lipoxins that are metabolically resistant to this pathway have been prepared, used in animal models to study LX activities, and tested as potential therapeutic agents in animals and humans.<ref name="pmid25895638"/><ref name="pmid26457057"/>

Similar to various other AA metabolites such as [[LTA4|LTA<sub>4</sub>]] and [[5-oxo-eicosatetraenoic acid]], cells and tissues may convert LXs to 20-hydroxy products by [[omega oxidation]]; they also have been shown to ligate LXA<sub>4</sub> to [[glutathione]] to form [[cysteine|cysteinyl-lipoxins]], initially LXC<sub>4</sub>, which is then sequentially metabolized to LXD<sub>4</sub> and LXE<sub>4</sub>.<ref name="pmid7706749">{{cite journal |vauthors=Powell WS, Chung D, Gravel S |title=5-Oxo-6,8,11,14-eicosatetraenoic acid is a potent stimulator of human eosinophil migration |journal=J. Immunol. |volume=154 |issue=8 |pages=4123–32 |year=1995 |doi=10.4049/jimmunol.154.8.4123 |pmid=7706749 |s2cid=35712418 |doi-access=free }}</ref> The role of these pathways in limiting or contributing to the activity of the LXs has not been fully evaluated.

=== Endocannabinoid system ===
The anti-inflammatory lipid lipoxin A<sub>4</sub> is an endogenous [[Allosteric regulation|allosteric]] enhancer of the [[Cannabinoid receptor type 1|CB1]] [[cannabinoid receptor]]. Lipoxin A<sub>4</sub> enhances the affinity of [[anandamide]] at this [[G protein-gated ion channel|receptor]] to exert cannabimimetic effects in the [[brain]], by allosterically enhancing AEA signaling and thereby potentiating the effects of this [[Cannabinoid#Endocannabinoids|endocannabinoid]] both ''in vitro'' and ''in vivo''. In addition to this, LXA<sub>4</sub> displays a CB1 receptor-dependent protective effect against [[Amyloid beta|β-amyloid]]-induced [[spatial memory]] impairment in mice.<ref>{{Cite journal|last1=Pamplona|first1=Fabricio A.|last2=Ferreira|first2=Juliano|last3=Menezes de Lima|first3=Octávio|last4=Duarte|first4=Filipe Silveira|last5=Bento|first5=Allisson Freire|last6=Forner|first6=Stefânia|last7=Villarinho|first7=Jardel G.|last8=Bellocchio|first8=Luigi|last9=Wotjak|first9=Carsten T.|date=2012-12-18|title=Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=109|issue=51|pages=21134–21139|doi=10.1073/pnas.1202906109|issn=0027-8424|pmc=3529012|pmid=23150578|bibcode=2012PNAS..10921134P|doi-access=free}}</ref>

===Lipoxin analogs===
Relatively stable, i.e. metabolically resistant, synthetic analogs of LXs and aspirin-triggered 15-epi-LXA<sub>4</sub>s can mimic many of the desirable anti-inflammatory, "pro-resolution" actions of native LXs and are being tested for clinical use.<ref name="pmid11478982">{{cite journal |vauthors=McMahon B, Mitchell S, Brady HR |title=Lipoxins: revelations on resolution |journal=Trends Pharmacol. Sci. |volume=22 |issue=8 |pages=391–5 |year=2001 |pmid=11478982 | doi= 10.1016/S0165-6147(00)01771-5 }}</ref><ref>{{Cite web|url=https://www.tampaliposuction.com/|title=Liposuction Tampa FL &#124; Lipo 360 & Body Sculpting|website=www.tampaliposuction.com}}</ref>  Structurally, these LX analogs often mimic the LXs in being or closely resembling a 20-carbon trihydroxy fatty acid, but are resistant to 15-hydroxyprostaglandin dehydrogenase metabolic inactivation by having a bulky or other structural modification near their 15-hydroxy residues.<ref name="pmid25895638"/> For example, certain analogs simply alter an LX's structure by:  replacing a hydrogen atom with a [[methyl]] residue at carbon 15 on LXA<sub>4</sub> to form 15-methyl-LXA<sub>4</sub>; changing the last 4 carbons of LXA<sub>4</sub> or 15-epi-LXA<sub>4</sub> to a 1-phenoxy residue or 1-phenoxy-4-fluoro residue to form 16-phenoxy-LX<sub>4</sub>, 15-epi-15-phenoxy-LXA<sub>4</sub>, 16-(para-fluoro-phenoxy-LXA<sub>4</sub>, or 15-epi-16-(para-fluoro-phenoxy-LXA<sub>4</sub>; and forming a bond between carbon 9 and carbon 14 of LXA<sub>4</sub> to form an internal phenyl ring analog termed aromatic LXA<sub>4</sub>; other, more complex structural analogs in development include 15-epi-LXA<sub>4</sub> analogs termed ZK-142 and ZK994.<ref name="pmid25895638"/>

==Biological activity==
===Cellular studies===
In the initial phases of many acute inflammatory responses, damaged tissues, invading pathogens, and other local events cause nearby cells to make and release arachidonic acid-derived pro-inflammatory metabolites such as: [[leukotriene]]s (LTs), e.g. LTB<sub>4</sub>, LTC<sub>4</sub>, LTD<sub>4</sub>, and LTE<sub>4</sub>; [[hydroxyeicosatetraenoic acid]]s (HETEs), e.g. [[5-HETE]] and [[12-HETE]]; and [[oxoeicosanoid]]s (oxo-ETE), e.g. [[5-oxo-eicosatetraenoic acid]] (5-oxo-ETE) and 12-oxo-ETE.  These metabolites proceed to act directly or indirectly to recruit circulating leukocytes, tissue macrophages, and tissue [[dendritic cell]]s to the disturbed tissue site. The consequential congregation of the various cell types promotes transcellular pathways in forming [[specialized pro-resolving mediators]] (SPMs), including the LXs, which then proceed to stimulate cellular and tissue responses that trend to reverse the actions of the pro-inflammatory mediators, dampen and reverse the inflammatory response, and initiate tissue repair.<ref name="pmid26688348">{{cite journal | vauthors = Basil MC, Levy BD | title = Specialized pro-resolving mediators: endogenous regulators of infection and inflammation | journal = Nature Reviews. Immunology | volume = 16 | issue = 1 | pages = 51–67 | year = 2016 | pmid = 26688348 | doi = 10.1038/nri.2015.4 | pmc = 5242505 }}</ref>

LXA<sub>4</sub> and 15-epi-LXA<sub>4</sub> are high-affinity [[receptor ligand]]s for and activators of the [[FPR2]] receptor. FPR2, which is now termed the ALX, ALX/FPR, or ALX/FPR2 receptor, is a [[G protein coupled receptor]] initially identified as a receptor for the leukocyte [[Chemotaxis|chemotactic factor]], [[N-Formylmethionine-leucyl-phenylalanine|N-formylmethionine-leucyl-phenylalanine]] (FMLP), based on its amino acid sequence similarity to the known FMLP receptor, [[FPR1]]. At least six homologues of this receptor are found in mice.  ALX/FPR is a promiscuous (i.e. interacting with diverse ligands) receptor that binds and is activated by other ligands including: '''a)''' various N-formyl oligopeptides that, like FMLP, are either released by microbes and [[mitochondria]] or are analogs of those released by microbes and mitochondria; '''b)''' microbe-derived non-formyl oligopeptides; '''c)''' certain polypeptides that are associated with the development of chronic [[amyloidosis]] and/or inflammation including [[serum amyloid A]] (SAA) proteins, a 42-amino acid peptide form [[amyloid beta]] termed Aβ42, [[humanin]], and a cleaved soluble fragment (amino acids 274–388) from the [[urokinase receptor]]; and '''d)''' other SPMs including [[resolvin]]s RvD1, RvD2, RvD5, AT-RvD1, and RvD3 (see [[Specialized pro-resolving mediators]]).<ref name="pmid25895638"/><ref name="pmid26457057"/><ref name="pmid19498085">{{cite journal | vauthors = Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM | title = International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family | journal = Pharmacological Reviews | volume = 61 | issue = 2 | pages = 119–61 | year = 2009 | pmid = 19498085 | pmc = 2745437 | doi = 10.1124/pr.109.001578 }}</ref>

LXA<sub>4</sub> and 15-epi-LXA<sub>4</sub> inhibit [[chemotaxis]], [[leukocyte extravasation#Transmigration|transmigration]], superoxide generation, [[NF-κB]] activation, and/or generation of pro-inflammatory cytokines (e.g. [[Interleukin 8|IL8]], [[Interleukin 13|IL13]], [[Interleukin 12|IL12]], and [[Interleukin 5|IL5]]) by neutrophils, eosinophils, [[monocyte]]s, [[innate lymphoid cell]]s, and/or [[macrophage]]s, as well as suppress proliferation and production of [[IgM]] and [[Immunoglobulin G|IgG]] antibodies by [[B lymphocyte]]s. These actions appear to involve stimulating anti-inflammatory signaling pathways, but also blocking the actions of other ALX/FPR ligands which simulate pro-inflammatory pathways.<ref name="pmid25895638"/><ref name="pmid26853678"/><ref name="pmid26688348"/><ref name=Chiang>{{cite journal | title=Anti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX |author1=Chiang N. |author2=Arita M. |author3=Serhan CN. |name-list-style=amp| journal= Prostaglandins, Leukotrienes and Essential Fatty Acids |volume=73 |pages=163–177 | year=2005 | pmid=16125378 | doi=10.1016/j.plefa.2005.05.003 | issue=3–4}}</ref> [[Transgene|Transgenic]] mice made to overexpress ALX/FPR exhibit markedly reduced inflammatory responses to diverse insults.<ref name="pmid16046112"/> LXA<sub>4</sub> and 15-epi-LXA<sub>4</sub>, when introduced by [[intrathecal administration]] into rodents, suppress the perception of inflammatory pain; this action may involve the ALX/FPR receptor shown to be present on the spinal [[astrocyte]]s of test animal and, based on studies using 15-epi-LXA, inhibition of the [[NALP1]] [[inflammasome]] signaling complex.<ref name="pmid26853678"/><ref name="pmid24076348">{{cite journal | vauthors = Li Q, Tian Y, Wang ZF, Liu SB, Mi WL, Ma HJ, Wu GC, Wang J, Yu J, Wang YQ | title = Involvement of the spinal NALP1 inflammasome in neuropathic pain and aspirin-triggered-15-epi-lipoxin A4 induced analgesia | journal = Neuroscience | volume = 254 | pages = 230–40 | year = 2013 | pmid = 24076348 | doi = 10.1016/j.neuroscience.2013.09.028 | s2cid = 207253564 }}</ref>

By mechanisms yet to be clearly identified, the two LXs also: a) stimulate the bacteria-killing capacity of leukocytes and airway epithelial cells; b) block production of the pro-inflammatory cytokine, [[TNFα]], while increasing production of the anti-inflammatory cytokine, [[CCR5]] by [[T lymphocyte]]s; c)' enhance the ability of monocytes and macrophages to [[phagocytos]] (i.e. ingest) and thereby remove potentially injurious [[apoptotic]] neutrophils and eosinophils from inflammatory sites (see [[Efferocytosis]]) either by direct effecting these cells or by stimulating [[NK cell]]s to do so; d) cause various cell types to reduce production of pro-inflammatory [[reactive oxygen species]] and expression of [[cell adhesion molecule]]s and increase production of the platelet inhibitor, [[PGI2]] and the vasodilator, [[nitric oxide]]; e) inhibit production of pro-inflammatory cytokines by [[mesangial cell]]s, [[fibroblast]]s, and other pro-inflammatory cell types; and f) reduce perception of pain due to inflammation.<ref name="pmid25895638"/><ref name="pmid26853678"/><ref name="pmid26688348"/><ref name="Chiang"/>

LXA<sub>4</sub> and 15-epi-LXA<sub>4</sub> also act by mobilizing transcription factors that regulate expression of various inflammation-regulating genes. LXA<sub>4</sub> stimulates various cell types to promote the entry of [[Nrf2]] into the nucleus and thereby to increase the expression of genes such as [[heme oxygenase-1]] (HMOX1), which increases production of the anti-inflammatory gaseous signaling agent, carbon monoxide, and genes involved in the synthesis of [[glutathione]], a product which neutralizes [[oxidative stress]] and oxidant-induced tissue damage.<ref name="pmid23826208">{{cite journal | vauthors = Chen XQ, Wu SH, Zhou Y, Tang YR | title = Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex | journal = PLOS ONE | volume = 8 | issue = 6 | pages = e67120 | year = 2013 | pmid = 23826208 | pmc = 3691153 | doi = 10.1371/journal.pone.0067120 | bibcode = 2013PLoSO...867120C | doi-access = free }}</ref><ref name="pmid25702137">{{cite journal | vauthors = Wu L, Li HH, Wu Q, Miao S, Liu ZJ, Wu P, Ye DY | title = Lipoxin A4 Activates Nrf2 Pathway and Ameliorates Cell Damage in Cultured Cortical Astrocytes Exposed to Oxygen-Glucose Deprivation/Reperfusion Insults | journal = Journal of Molecular Neuroscience | volume = 56 | issue = 4 | pages = 848–57 | year = 2015 | pmid = 25702137 | doi = 10.1007/s12031-015-0525-6 | s2cid = 14077073 }}</ref> Metabolically resistant structural analogs of LXB<sub>4</sub> and 15-epi-LXA<sub>4</sub> inhibit formation of [[peroxynitrite]] (i.e. ONOO<sup>−</sup>) to attenuate the mobilization of [[NFκB]] and [[AP-1 transcription factor]]s by reducing their accumulation in the nucleus of neutrophils, monocytes, and lymphocytes; NFκB and AP-1 increase expression of pro-inflammatory genes. The two LXBs also trigger activation of Suppressor of cytokine signaling proteins (see [[SOCS]] proteins) which, in turn, inhibit activation of [[STAT protein]] transcription factors which up-regulate many genes making pro-inflammatory products.<ref name="pmid26457057"/>

LXA<sub>4</sub> and 15-epi-LXA<sub>4</sub> are also high-affinity [[receptor antagonist|antagonists]] of the [[cysteinyl leukotriene receptor 1]] for which leukotrienes (LT) [[Leukotriene C4|LTC<sub>4</sub>]], [[Leukotriene D4|LTD<sub>4</sub>]], and [[Leukotriene E4|LTE<sub>4</sub>]] are [[agonist]]s, i.e. the three leukotrienes bind to and thereby stimulate smooth muscle contraction, eosinophil chemotactaxis, mucous gland secretion, and various other pro-[[Allergy|allergic]] responses in the cells of lung, skin, and other tissues.<ref name="pmid16046112"/><ref name="pmid11141472">{{cite journal | vauthors = Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN | title = Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses | journal = The American Journal of Pathology | volume = 158 | issue = 1 | pages = 3–9 | year = 2001 | pmid = 11141472 | pmc = 1850279 | doi = 10.1016/S0002-9440(10)63937-5 }}</ref> (CysLT1 and ATX/FPR2 have an amino acid sequence identity of 47%.<ref name="pmid11141472"/>) The ability of these LXs to block the actions of the three LTs may contribute to their ability to resolve allergic reactions; for example, LXA4 relaxes the smooth muscle contraction caused by the cysteinyl leukotrienes in the hamster [[cheek pouch]] assay and a metabolically resistant 15-epi-LXAA<sub>4</sub> analog potently inhibits [[allergen]]-driven airway hypersensitivity and inflammation in a mouse model.<ref name="pmid16046112"/><ref name="pmid11141472"/><ref name="pmid18437962">{{cite journal | vauthors = Wan KS, Wu WF | title = Eicosanoids in asthma | journal = Acta Paediatrica Taiwanica = Taiwan Er Ke Yi Xue Hui Za Zhi | volume = 48 | issue = 6 | pages = 299–304 | year = 2007 | pmid = 18437962 }}</ref>

At higher concentrations (>30 nmole/liter), LXA<sub>4</sub> binds to [[AHR]], the arylhydrocarbon receptor; following this binding, AHR enters the nucleus, where it joins with AhR nuclear translocator (ARNT). The AHR/ARNT complex binds to [[xenobiotic response element]]s to activate transcription of genes, most of which are involved primarily in [[xenobiotic]] metabolism. These genes include [[SOCS2]] (i.e. suppressor of cytokine signaling 2), [[CYP1A1]], [[CYP1A2]], [[CYP1B1]], [[glutathione S-transferase]] Ya subunit, quinone oxidoreductase, [[UDP-glucuronosyltransferase]] and [[aldehyde dehydrogenase 3 family, member A1]]. This LXA<sub>4</sub> activity has been demonstrated only in murine cells.<ref>{{cite journal | pmid = 10360957 | doi=10.1021/bi982861e | volume=38 | title=Lipoxin A4: a new class of ligand for the Ah receptor. | date=Jun 1999 | journal=Biochemistry | pages=7594–600 | vauthors=Schaldach CM, Riby J, Bjeldanes LF| issue=23 }}</ref><ref name="pmid27837747">{{cite journal | vauthors = Bennett M, Gilroy DW | title = Lipid Mediators in Inflammation | journal = Microbiology Spectrum | volume = 4 | issue = 6 | year = 2016 | pages = 343–366 | pmid = 27837747 | doi = 10.1128/microbiolspec.MCHD-0035-2016 | isbn = 9781555819187 | url =http://discovery.ucl.ac.uk/1530515/1/Bennett_Lipid%20Mediators%20in%20Inflammation.pdf }}</ref>

LXA<sub>4</sub> binds to and activates [[estrogen receptor alpha]], with an IC50 of 46nM. LXA<sub>4</sub> and ATLa were shown to activate transcriptional and functional (alkaline phosphatase and proliferation) responses via ERa in human [[Endometrium|endometrial]] epithelial cells ''in vitro'' and in mouse uterine tissue ''in vivo''. Interestingly, LXA<sub>4</sub>  also demonstrated antiestrogenic potential, significantly attenuating E2-induced activity.  In a mouse model of endometriois physiologically relevant concentrations of ATLa caused a reduction in lesion size and impacted the production of inflammatory mediators. Molecules regulated via ERa were also impacted, implying that Lipoxin A<sub>4</sub> and analogues, inhibiting both proliferative and inflammatory pathways, might be considered as potential therapeutics.<ref>{{cite journal | vauthors = Russell R, Gori I, Pellegrini C, Kumar R, Achtari C, Canny GO | date = Dec 2011 | title = Lipoxin A4 is a novel estrogen receptor modulator | journal = FASEB J | volume = 25 | issue = 12| pages = 4326–37 | doi = 10.1096/fj.11-187658 | doi-access = free | pmid = 21885654 | s2cid = 2715055 }}</ref><ref name="pmid10360957">{{cite journal | vauthors = Schaldach CM, Riby J, Bjeldanes LF | title = Lipoxin A4: a new class of ligand for the Ah receptor | journal = Biochemistry | volume = 38 | issue = 23 | pages = 7594–600 | year = 1999 | pmid = 10360957 | doi = 10.1021/bi982861e }}</ref>

The actions of LXB<sub>4</sub> and 15-epi-LXB<sub>4</sub> have been far less well defined than those of their LXA<sub>4</sub> analogs. Their mechanism of stimulating target cells (e.g. receptors) is not known. One or both of these analogs have been shown to inhibit the recruitment of neutrophils to sites of inflammation, inhibit the cytotoxicity of [[NK cell]]s, stimulate the recruitment of monocytes to inflammatory sites, enhance macrophage phagocytosis, and suppress the perception of inflammatory pain in rodents.<ref name="pmid25895638"/><ref name="pmid26853678"/><ref name="pmid27121596">{{cite journal | vauthors = Elajami TK, Colas RA, Dalli J, Chiang N, Serhan CN, Welty FK | title = Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling | journal = FASEB Journal | volume = 30 | issue = 8 | pages = 2792–801 | year = 2016 | pmid = 27121596 | doi = 10.1096/fj.201500155R | doi-access = free | pmc = 4970606 }}</ref>

===Animal model studies===
====Noninfectious inflammation====
One or more of the lipoxins or their analogs have been demonstrated to suppress, limit severity, and/or increase survival in multiple inflammatory and allergic diseases in mouse and rat model studies. These studies include models of experimentally evoked [[endometriosis]],<ref>{{cite journal | vauthors = Kumar R, Clerc AC, Gori I, Russell R, Pellegrini C, Govender L, Wyss JC, Golshayan D, Canny GO  | title = Lipoxin A4 Prevents the Progression of De Novo and Established Endometriosis in a Mouse Model by Attenuating Prostaglandin E2 Production and Estrogen Signaling | journal = PLOS ONE | volume = 9 | issue = 2 | pages = e89742, 1–14 | date = February 2014 | pmid = 24587003 | doi =10.1371/journal.pone.0089742| pmc = 3933674 | bibcode = 2014PLoSO...989742K | doi-access = free }}</ref> [[colitis]], [[peritonitis]], [[pancreatitis]], [[kidney]] inflammation and [[glomerulonephritis]], lung [[asthma]], acid-induced lung injury, [[cystic fibrosis]], [[pleurisy]], brain inflammation and the inflammatory component of [[Alzheimer's disease]], vascular ischemia-reperfusion injuries to various organs including the heart and hind limb, [[transplant rejection]] of heart, kidney, and [[bone marrow]], [[arthritis]], [[dermatitis]], [[periodontitis]], [[cornea]] inflammation, and inflammation-based pain, [[hyperalgesia]],<ref name="pmid25895638" /><ref name="pmid26457057" /> and [[diabetes]]/[[cardiovascular disease]].<ref>{{Cite journal |last=Fu |first=Ting |last2=Mohan |first2=Muthukumar |last3=Bose |first3=Madhura |last4=Brennan |first4=Eoin P. |last5=Kiriazis |first5=Helen |last6=Deo |first6=Minh |last7=Nowell |first7=Cameron J. |last8=Godson |first8=Catherine |last9=Cooper |first9=Mark E. |last10=Zhao |first10=Peishen |last11=Kemp-Harper |first11=Barbara K. |last12=Woodman |first12=Owen L. |last13=Ritchie |first13=Rebecca H. |last14=Kantharidis |first14=Phillip |last15=Qin |first15=Cheng Xue |date=2024-11-20 |title=Lipoxin A<sub>4</sub> improves cardiac remodeling and function in diabetes-associated cardiac dysfunction |url=https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02501-x |journal=Cardiovascular Diabetology |language=en |volume=23 |issue=1 |doi=10.1186/s12933-024-02501-x |issn=1475-2840 |pmc=11577589 |pmid=39563316 |doi-access=free}}</ref>

====Infection-related inflammation====
Lipoxins have protective effects in animal models of infection-based inflammation: 

* LXA<sub>4</sub> and a LXA<sub>4</sub> analog decreased systemic inflammation and improved survival in rat models of [[gram-negative bacteria]]l [[sepsis]];<ref name="pmid26688348" /><ref name="pmid25476955">{{cite journal | vauthors = Wu B, Walker J, Spur B, Rodriguez A, Yin K | title = Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 94 | pages = 55–64 | year = 2015 | pmid = 25476955 | doi = 10.1016/j.plefa.2014.11.005 }}</ref> 
* 15-epi-LXA<sub>4</sub> suppressed the lung injury (i.e., shock lung or [[acute respiratory distress syndrome]]) caused by intraperitoneal injection of ''[[Escherichia coli]]'' in mice; 
* transgenic mice made deficient in lipoxin synthesis by deletion of their ''Alox5'' gene were more susceptible to the inflammatory and lethal effects of ''[[Toxoplasma gondii]]'' and were rescued from these defects by LXA4<sub>4</sub>;<ref name="pmid24400794">{{cite journal | vauthors = Russell CD, Schwarze J | title = The role of pro-resolution lipid mediators in infectious disease | journal = Immunology | volume = 141 | issue = 2 | pages = 166–73 | year = 2014 | pmid = 24400794 | pmc = 3904237 | doi = 10.1111/imm.12206 }}</ref> 
* LXA<sub>4</sub> restored macrophage function caused by [[respiratory syncytial virus]] in transgenic mice made deficient of lipoxin synthesis by ''Alox5'' gene deletion;<ref name="pmid26688348" /> 
* LXA<sub>4</sub> ameliorated infectious [[periodontitis]] in rabbit and porcine models;<ref name="pmid26688348" /> 
* 15-epi-LXA<sub>4</sub> decreased parasite blood levels, decrease cardiac inflammation, and increase survival in a mouse model of ''[[Trypanosoma cruzi]]''-induced [[Chagas disease]];<ref name="pmid24400794" /> 
** 15-epi-LXA<sub>4</sub> prolonged survival in a mouse model of ''[[Plasmodium berghei]]''-induced cerebral malaria;<ref name="pmid24400794" /> and 
* LXA<sub>4</sub> shortens the duration of the allergic response to the parasitic infestation, ''[[Angiostrongylus costaricensis]]''.<ref name="pmid26688348" />

However, lipoxins also produced harmful effects in these models: aerosol infection with ''[[Mycobacterium tuberculosis]]'' in transgenic mice defective in ALOX5, which contributes to LX synthesis, exhibited far less severe inflammation and better survival than control mice;<ref name="pmid24400794" /> and  treatment of the transgenic mice with oral LXA<sub>4</sub> reversed the protective effect of ALOX5 deletion.<ref name="pmid24400794" />

===Human studies===
====Preclinical studies====
LXs and epi-LXs have been detected in various human tissues undergoing a wide range of inflammatory reactions, allergic reactions, and other conditions such as in the blood of patients undergoing coronary angioplasty or strenuous exercise.<ref name="pmid25895638"/><ref name="pmid26853678"/><ref name="pmid27121596"/> LXA<sub>4</sub> inhibits the-bronchial contracting action of LTC4 and relaxes pre-contracted bronchi in asthmatic individuals.<ref name="pmid16046112"/>

[[Kaposi's sarcoma-associated herpesvirus]] (KSHV) causes the malignant transformation of human cells and is responsible for [[Kaposi's sarcoma]] and [[primary effusion lymphoma]], two cancers which afflict in particular humans infected with [[HIV]]. Studies in human Kaposi sarcoma and primary effusion lymphoma cells find that: 

* KSHV promotes the production of pro-inflammatory cytokines, lipoxygenases, cyclooxygenase, and metabolites of the latter two classes of enzymes while suppressing production of anti-inflammatory signaling agents such as LXA<sub>4</sub>, apparently as a strategy to promote its latency and malignant transforming ability; 
* Kaposi sarcoma and primary effusion lymphoma cells express the ALX/FPR receptor; and 
* treatment of the latter cells with LXA<sub>4</sub> or 15-epi-LXA<sub>4</sub> reverses this pro-malignancy profile of pro-inflammatory signaling by an ALX/FPR-dependent mechanism. 

These studies suggest that the two LXs or their analogs should be tested for possible use for treating the two malignancies.<ref name="pmid26457057" /><ref name="pmid27681120">{{cite journal | vauthors = Chandrasekharan JA, Huang XM, Hwang A, Sharma-Walia N | title = Altering the anti-inflammatory lipoxin microenvironment: a new insight into KSHV pathogenesis | journal = Journal of Virology | volume = 90| pages = 11020–11031| year = 2016 | issue = 24 | pmid = 27681120 | doi = 10.1128/JVI.01491-16 | pmc = 5126361 }}</ref>

====Clinical studies====
In a [[randomized controlled trial]], topical application of 15-epi-LXA<sub>4</sub> or a comparatively stable analog of LXB<sub>4</sub>, 15''R/S''-methyl-LXB<sub>4</sub>, reduced the severity of [[eczema]] in a study of 60 infants.<ref name="pmid22834636">{{cite journal | vauthors = Wu SH, Chen XQ, Liu B, Wu HJ, Dong L | title = Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema | journal = The British Journal of Dermatology | volume = 168 | issue = 1 | pages = 172–8 | year = 2013 | pmid = 22834636 | doi = 10.1111/j.1365-2133.2012.11177.x | s2cid = 31721094 }}</ref><ref name="pmid25061854">{{cite journal | vauthors = Aslam I, Sandoval LF, Feldman SR | title = What's new in the topical treatment of allergic skin diseases | journal = Current Opinion in Allergy and Clinical Immunology | volume = 14 | issue = 5 | pages = 436–50 | year = 2014 | pmid = 25061854 | doi = 10.1097/ACI.0000000000000093 | s2cid = 20136504 }}</ref>

As of 2015, BLXA<sub>4</sub>, a lipoxin analog, was undergoing a phase 1 clinical trial for treating oral [[gingivitis]].<ref name="pmid26457057"/><ref>{{Cite report |url=https://clinicaltrials.gov/study/NCT02342691 |title=A Phase 1 &#x2F; 2 Clinical Trial to Assess the Safety and Preliminary Efficacy of Lipoxin Analog BLXA4-ME Oral Rinse for the Treatment of Gingivitis |last=The Forsyth Institute |date=2023-11-29 |publisher=clinicaltrials.gov |issue=NCT02342691}}</ref>

==See also==
* [[Epi-lipoxins]]
* [[Specialized pro-resolving mediators]]
* [[15-Hydroxyeicosatetraenoic acid]]

==References==
{{Reflist|2}}

==External links==
* {{MeshName|Lipoxins}}

{{Eicosanoids}}
{{Aryl hydrocarbon receptor modulators}}

[[Category:Eicosanoids]]