A lipoxin (LX or Lx), an acronym for
lipoxygenase
Lipoxygenases () are a family of (non-heme) iron-containing enzymes most of which catalyze the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene into cell signaling agents that serve diverse roles as auto ...
interaction product, is a bioactive
autacoid
Autacoids or "autocoids" are biological factors (molecules) which act like local hormones, have a brief duration, and act near their site of synthesis. The word ''autacoid'' comes from the Greek words "autos" (self) and "acos" (relief; i.e., drug) ...
metabolite of
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
made by various cell types. They are categorized as
nonclassic eicosanoid Nonclassic eicosanoids are biologically active signaling molecules made by oxygenation of twenty-carbon fatty acids other than the classic eicosanoids.
Terminology
:
"Eicosanoid" is the collective
term for oxygenated derivatives of three differe ...
s and members of the
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
(SPMs) family of
polyunsaturated fatty acid
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...
(PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve,
inflammatory response
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...
s. Initially, two lipoxins were identified, lipoxin A
4 (LXA
4) and LXB
4, but more recent studies have identified
epimer
In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is ...
s of these two LXs: the
epi-lipoxins Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-L ...
, 15-epi-LXA
4 and 15-epi-LXB
4 respectively.
History
LXA
4 and LXB
4 were first described by Serhan, Hamberg, and the Nobel laurate
Samuelsson in 1984.
They reported that human blood
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
, when stimulated, make these two lipoxins and that neutrophils, when stimulated by either of the LXs, mounted
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
anion (O
2−) generation and
degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulo ...
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
4 and LXB
4, act primarily to dampen and resolve inflammation, i.e. they are anti-inflammatory
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
agents.
Biochemistry
Lipoxins are derived enzymatically from
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
, an
ω-6 fatty acid. Structurally, they are defined as arachidonic acid metabolites that contain three
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
residues (also termed hydroxy residues) and four
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s. This structural definition distinguishes them from other SPMs such as the
resolvins
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar t ...
,
neuroprotectin
Neuroprotectin D1 (NPD1) (10''R'',17''S''-dihydroxy-4''Z'',7''Z'',11''E'',13''E'',15''Z'',19''Z''-docosahexaenoic acid) also known as Protectin D1 (PD1) is a docosanoid derived from the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), ...
s, and
maresin
Maresin 1 (MaR1 or 7''R'',14''S''-dihydroxy-4''Z'',8''E'',10''E'',12''Z'',16''Z'',19''Z''-docosahexaenoic acid) is a macrophage-derived mediator of inflammation resolution coined from macrophage mediator in resolving inflammation. Maresin 1, an ...
s, which are metabolites of the
omega 3 fatty acids
Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chem ...
,
eicosapentaenoic acid
Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-c ...
or
docosahexaenoic acid
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...
, as well as a range of metabolites derived from other PUFAs (see
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
). All of these other SPMs have activities and functions similar, although not necessarily identical, to the lipoxins .
Synthesis
Formation of LXs is conserved across a broad range of animal species from fish to humans.
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
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
, 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
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
activity which in humans includes
ALOX15
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
,
ALOX12, aspirin-treated
cyclooxygenase 2
Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene. ...
, and
cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
s of the microsomal, mitochondrial, or bacterial subclasses.
ALOX15B
Arachidonate 15-lipoxygenase type II is an enzyme that in humans is encoded by the ''ALOX15B'' gene. ALOX15B, also known as 15-lipoxygenase-2 (15-LO-2 or 15-LOX-2), is distinguished from its related oxygenase, ALOX15 or 15-lipoxygenase-1.
Funct ...
may also conduct this metabolism. The other enzyme attack point forms a 5,6-
epoxide
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
which is resolved to either 5,6-dihydroxy-eicosatetraenoate or 5-hydroxy eicosatetraenoate products; this step catalyzed by
5-lipoxygenase
Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
(ALOX5). Accordingly, these double oxygenations yield either 5,6,15-trihydroxy- or 5,14,15-trihydroxy-eicosatetraenoates.
The double oxygenations may be conducted within a single cell type which possess 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.
For example, LXs are formed by platelets which, lacking ALOX5, cannot synthesize them. Rather,
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
form, the 5,6-epoxide,
leukotriene A4
Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 (leukotriene B)) and LTC4 (leukotriene C4).
Biosynthesis of Leukotriene A4
Following the biosynthesis of eicosanoid, triggered as a result of infection or ...
(LTA
4), via ALOX5 and passed it to platelets that then reduce it a 5,6-dihydroxy-eicosateteraenoate product and further metabolize it through ALOX12 to form the 15-hydroxy product, LXA
4.
The two LXs are distinguished form their 15-epi-LTX epimers by their structural formulae:
*LxA
4: 5''S'',6''R'',15''S''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid
*LxB
4: 5''S'',14''R'',15''S''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatetraenoic acid
*15-epi-LxA
4: 5''S'',6''R'',15''R''-trihydroxy-7''E'',9''E'',11''Z'',13''E''-eicosatetraenoic acid
*15-epi-LxB
4: 5''S'',14''R'',15''R''-trihydroxy-6''E'',8''Z'',10''E'',12''E''-eicosatrienoic acid
Note that the two LXs have their 15-hydroxyl residues in the ''S''
chirality
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from ...
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
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
s; these enzymes form almost entirely or partly 15''R''-hydroxy products.
(15-Epi-LTA4
4 and 15-epi-LTB4
4 are sometimes termed AT-LxA
4 and AT-LxB
4, respectively, when acknowledging their formation by aspirin-treated cyclooxygenase 2, i.e. by Aspirin-Triggered cyclooxygenase 2.)
In addition to the pathways cited above, other transcellular metabolic routes have been shown to make LXs. For example,
5-lipoxygenase
Arachidonate 5-lipoxygenase, also known as ALOX5, 5-lipoxygenase, 5-LOX, or 5-LO, is a non-heme iron-containing enzyme (EC 1.13.11.34) that in humans is encoded by the ''ALOX5'' gene. Arachidonate 5-lipoxygenase is a member of the lipoxygenase fa ...
(i.e. (ALOX5) in neutrophils and
15-lipoxygenase
ALOX15 (also termed arachidonate 15-lipoxygenase, 15-lipoxygenase-1, 15-LO-1, 15-LOX-1) is, like other lipoxygenases, a seminal enzyme in the metabolism of polyunsaturated fatty acids to a wide range of physiologically and pathologically importa ...
-1 (i.e. ALOX15) in immature erythrocytes and reticulocytes operate in series to form LxA4
4 and LxB4
4; this pathway also occurs in serial interactions between neutrophils and eosinophils; between
epithelium
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
or M2
Macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s/monocytes and neutrophils; and
endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
or skeletal muscle and neutrophils.
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
IFN-γ
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...
and
IL-1β
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
further increase production of the lipoxins (as well as other anti-inflammatory PUFA metabolites and proteins, e.g.
IL4.
[ Invited review article.]
Further metabolism
LXs are rapidly metabolized, mainly by macrophages, to inactive products by being oxidized at carbon 15 to form 15-
keto (also termed 15-oxo) LX products by a
15-hydroxyprostaglandin dehydrogenase; 15-oxo-LXA
4 may be further metabolized to 13,14-dihydro-LXA
4 by an
oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
. 15-Epi-LXA
4 and 15-epi-LXB
4 are more resistant to the dehydrogenation enzyme than their LX epimers.
In consequence of the operation of this
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
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.
Similar to various other AA metabolites such as
LTA4
Leukotriene A4 (LTA4) is a leukotriene, and is the precursor for the productions of LTB4 ( leukotriene B)) and LTC4 (leukotriene C4).
Biosynthesis of Leukotriene A4
Following the biosynthesis of eicosanoid, triggered as a result of infection o ...
and
5-oxo-eicosatetraenoic acid, cells and tissues may convert LXs to 20-hydroxy products by
omega oxidation Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of involving the β carbon, involves the oxidation of the ω carbon (the carbon most dist ...
; they also have been shown to ligate LXA
4 to
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
to form
cysteinyl-lipoxins, initially LXC
4, which is then sequentially metabolized to LXD
4 and LXE
4.
The role of these pathways in limiting or contributing to the activity of the LXs has not been fully evaluated.
Endocannabinoid system
It is found that the anti-inflammatory lipid lipoxin A
4 is an endogenous
allosteric
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
enhancer of the
CB1 cannabinoid receptor
Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system a class of cell membrane receptors in the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid recepto ...
. Lipoxin A
4 enhance the affinity of
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...
at this
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
to exert cannabimimetic effects in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
, by allosterically enhancing AEA signaling and thereby potentiating the effects of this
endocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
both
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
and
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
. In addition to this, lipoxin A
4 display a CB1 receptor-dependent protective effect against
β-amyloid
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
-induced
spatial memory
In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...
impairment in mice.
Lipoxin analogues
Relatively stable, i.e. metabolically resistant, synthetic analogues of LXs and aspirin-triggered 15-epi-LXA
4s can mimic many of the desirable anti-inflammatory, "pro-resolution" actions of native LXs and are being tested for clinical use.
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.
For example, certain analogs simply alter an LX's structure by: replacing a hydrogen atom with a
methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
residue at carbon 15 on LXA
4 to form 15-methyl-LXA
4; changing the last 4 carbons of LXA
4 or 15-epi-LXA
4 to a 1-phenoxy residue or 1-phenoxy-4-fluoro residue to form 16-phenoxy-LX
4, 15-epi-15-phenoxy-LXA
4, 16-(para-fluoro-phenoxy-LXA
4, or 15-epi-16-(para-fluoro-phenoxy-LXA
4; and forming a bond between carbon 9 and carbon 14 of LXA
4 to form an internal phenyl ring analog termed aromatic LXA
4; other, more complex structural analogs in development include 15-epi-LXA
4 analogs termed ZK-142 and ZK994.
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
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid (AA) and the essential fatty acid eicosapentaenoic acid (EPA) by the enzyme arachidonate 5-lipoxygenase.
Leukotrienes ...
s (LTs), e.g. LTB
4, LTB
4, LTC
4, LTD
4, and LTE
4;
hydroxyeicosatetraenoic acid Hydroxyeicosatetraenoic acid may refer to:
* 5-Hydroxyeicosatetraenoic acid
* 12-Hydroxyeicosatetraenoic acid (12-HETE)
* 15-Hydroxyeicosatetraenoic acid
* 20-Hydroxyeicosatetraenoic acid (20-HETE)
* 19-Hydroxyeicosatetraenoic acid (see 20-Hydro ...
s (HETEs), e.g.
5-HETE and
12-HETE; and
oxoeicosanoid The oxoeicosanoids are nonclassic eicosanoids, derived from arachidonic acid (AA).
For example, Lipoxygenase produces 5-HETE from AA; a dehydrogenase then produces 5-oxo-eicosatetraenoic acid, an oxoeicosanoid, from 5-HETE.
They are similar to ...
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
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
s to the disturbed tissue site. The consequential congregation of the various cell types promotes transcellular pathways in forming
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
(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.
LXA
4 and 15-epi-LXA
4 are high affinity
receptor ligand
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...
s for and activators of the
FPR2
N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the ''FPR2'' gene and is activated to regulate cell function b ...
receptor. FPR2, which is now termed the ALX, ALX/FPR, or ALX/FPR2 receptor, is a
G protein coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
initially identified as a receptor for the leukocyte
chemotactic factor
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
,
N-Formylmethionine-leucyl-phenylalanine
''N''-Formylmethionyl-leucyl-phenylalanine (fMLF, fMLP or ''N''-formyl-met-leu-phe) is an ''N''- formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic factor and ...
(FMLP), based on its amino acid sequence similarity to the known FMLP receptor,
FPR1
Formyl peptide receptor 1 (FPR1, FPR1 receptor, fMet-Leu-Phe receptor 1, FMLP receptor 1, or N-formylmethionyl-leucyl-phenylalanine receptor 1) is a cell surface receptor protein that in humans is encoded by the ''formyl peptide receptor 1'' (''F ...
. 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
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
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
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
and/or inflammation including
Serum amyloid A
Serum amyloid A (SAA) proteins are a family of apolipoproteins associated with high-density lipoprotein (HDL) in plasma. Different isoforms of SAA are expressed constitutively (constitutive SAAs) at different levels or in response to inflammato ...
(SAA) proteins), a 42-amino acid peptide form
Amyloid beta
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
termed Aβ42,
Humanin
Humanin is a micropeptide encoded in the mitochondrial genome by the 16S ribosomal RNA gene, MT-RNR2. Its structure contains a three-turn α-helix, and no symmetry.
In ''in vitro'' and animal models, it appears to have cytoprotective effects. ...
, and a cleaved soluble fragment (amino acids 274-388) from the
Urokinase receptor
The Urokinase receptor, also known as urokinase plasminogen activator surface receptor (uPAR) or CD87 (Cluster of Differentiation 87), is a protein encoded in humans by the PLAUR gene. It is a multidomain glycoprotein tethered to the cell membran ...
; and d) other SPMs including
Resolvin
Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as docosapentaenoic acid (DPA) and clupanodonic acid. As autacoids similar t ...
s RvD1, RvD2, RvD5, AT-RvD1, and RvD3 (see
specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
).
LXA
4 and 15-epi-LXA
4 inhibit
chemotaxis
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
,
transmigration, superoxide generation,
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
activation, and/or generation of pro-inflammatory cytokines (e.g.
IL8,
IL13,
IL12, and
IL5) by neutrophils, eosinophils,
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also inf ...
s,
Innate lymphoid cell
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling mo ...
s, and/or
macrophages
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
, as well as suppress proliferation and production of
IgM
Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...
and
IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
antibodies by
B lymphocyte
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
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.
Transgenic
A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
mice made to overexpress ALX/FPR exhibit markedly reduced inflammatory responses to diverse insults.
LXA
4 and 15-epi-LXA
4, when introduced by
Intrathecal administration
Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF) and is useful in spinal anesthesia, chemotherapy, or pain man ...
into rodents, suppress the perception of inflammatory pain; this action may involve the ALX/FPR receptor shown to be present on the spinal
astrocyte
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
s of test animal and, based on studies using 15-epi-LXA, inhibition of the
NALP1
NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans. NLRP1 was the first protein shown to form an inflammasome. Material was copied from this source, which is available under Creative Commons Attribution 4. ...
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
signaling complex.
By mechanisms yet to be clearly identified, the two LX's also: a) stimulate the bacteria-killing capacity of leukocytes and airway epithelial cells; b) block production of the pro-inflammatory cytokine,
TNFα
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, while increasing production of the anti-inflammatory cytokine,
CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the ''CCR5'' gene that encodes the CCR5 pro ...
by
T lymphocyte
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
s; c)' enhance the ability of monocytes and macrophages to
phagocytos (i.e. ingest) and thereby remove potentially injurious
apoptotic
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
neutrophils and eosinophils from inflammatory sites (see
Efferocytosis In cell biology, efferocytosis (from ''efferre'', Latin for 'to take to the grave', 'to bury') is the process by which apoptotic cells are removed by phagocytic cells. It can be regarded as the 'burying of dead cells'.
During efferocytosis, the cel ...
) either by direct effecting these cells or by stimulating
NK cell
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
s to do so; d) cause various cell types to reduce production of pro-inflammatory
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
and expression of
Cell adhesion molecule
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s and increase production of the platelet inhibitor,
PGI2
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
When used as a drug, it is also known as epoprosteno ...
and the vasodilator,
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
; e) inhibit production of pro-inflammatory cytokines by
mesangial cell
Mesangial cells are specialised cells in the kidney that make up the mesangium of the glomerulus. Together with the mesangial matrix, they form the vascular pole of the renal corpuscle. The mesangial cell population accounts for approximately 30 ...
s,
fibroblast
A fibroblast is a type of cell (biology), biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and plays a critical role in wound ...
s, and other pro-inflammatory cell types; and f) reduce perception of pain due to inflammation.
LXA
4 and 15-epi-LTA
4 also act by mobilizing transcription factors that regulate expression of various inflammation-regulating genes. LXA
4 stimulates various cell types to promote the entry of
Nrf2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...
into the nucleus and thereby to increase the expression of genes such as
heme oxygenase-1
Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.
There are many heme degrading enzymes in nature. In general, only ...
(HMOX1), which increases production of the anti-inflammatory gaseous signaling agent, carbon monoxide, and genes involved in the synthesis of
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...
, a product which neutralizes
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
and oxidant-induced tissue damage.
Metabolically resistant structural analogs of LXB
4 and 15-epi-LXA
4 inhibit formation of
Peroxynitrite
Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate,
Preparation
Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide:
:
It is prepared by the react ...
(i.e. ONOO
−) to attenuate the mobilization of
NFκB and
AP-1 transcription factor
Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli, including cytokines, growth factors, stress, and bacterial and viral infections. AP-1 controls a number of cellular process ...
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
SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway.
Genes
* CISH
* SOCS1
* SOCS2
* SOCS3
* SOCS4
* SOCS5
* SOCS6
* SOCS7
Suppressor of cytokine signaling 7 is a pro ...
proteins) which, in turn, inhibit activation of
STAT protein
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
transcription factors which up-regulate many genes making pro-inflammatory products.
LXA
4 and 15-epi-LXA
4 are also high affinity
antagonists
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the
Cysteinyl leukotriene receptor 1
Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT) (see leukotrienes#Cysteinyl leukotrienes). CYSLTR1, by binding these cysteinyl LTs (CysLTs; viz, LTC4, LTD4, and to a much lesser extent, LTE4) c ...
for which leukotrienes (LT)
LTC4
Leukotriene C4 (LTC4) is a leukotriene. LTC4 has been extensively studied in the context of allergy and asthma. In cells of myeloid origin such as mast cells, its biosynthesis is orchestrated by translocation to the nuclear envelope along with c ...
,
LTD4
Leukotriene D4 (LTD4) is one of the leukotrienes. Its main function in the body is to induce the contraction of smooth muscle, resulting in bronchoconstriction and vasoconstriction. It also increases vascular permeability. LTD4 is released by bas ...
, and
LTE4
Leukotriene E4 (LTE4) is a cysteinyl leukotriene involved in inflammation. It is known to be produced by several types of white blood cells, including eosinophils, mast cells, tissue macrophages, and basophils, and recently was also found to be ...
are
agonists
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...
, i.e. the three leukotrienes bind to and thereby stimulate smooth muscle contraction, eosinophil chemotactaxis, mucous gland secretion, and various other pro-
allergic
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
responses in the cells of lung, skin, and other tissues.
(CysLT1 and ATX/FPR2 have an amino acid sequence identity of 47%.
) 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
Cheek pouches are pockets on both sides of the head of some mammals between the jaw and the cheek. They can be found on mammals including the platypus, some rodents, and most monkeys, as well as the marsupial koala. The cheek pouches of chipmunks ...
assay and a metabolically resistant 15-epi-LXAA
4 analog potently inhibits
allergen
An allergen is a type of antigen that produces an abnormally vigorous immune response in which the immune system fights off a perceived threat that would otherwise be harmless to the body. Such reactions are called allergies.
In technical terms ...
-driven airway hypersensitivity and inflammation in a mouse model.
At higher concentrations (>30 nmole/liter), LXA
4 binds to
AHR
Ahr () is a river in Germany, a left tributary of the Rhine. Its source is at an elevation of approximately above sea level in Blankenheim in the Eifel, in the cellar of a timber-frame house near the castle of Blankenheim. After it crosses fro ...
, 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 elements to activate transcription of genes, most of which are involved primarily in xenobiotic metabolism. These genes include
SOCS2
Suppressor of cytokine signaling 2 is a protein that in humans is encoded by the ''SOCS2'' gene.
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signalling (SOCS), family. SSI family member ...
(i.e. suppressor of cytokine signaling 2),
CYP1A1
Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein
that in humans is encoded by the ''CYP1A1'' gene.
The protein is a member of the cytochrome P450 superfamily of enzymes.
Function
Metabolism of xenobiotics and drugs
CYP1A1 ...
,
CYP1A2
Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene.
Function
...
,
CYP1B1
Cytochrome P450 1B1 is an enzyme that in humans is encoded by the ''CYP1B1'' gene.
Function
CYP1B1 belongs to the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved i ...
,
glutathione S-transferase
Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) to x ...
Ya subunit, quinone oxidoreductase,
UDP-glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
and
Aldehyde dehydrogenase 3 family, member A1
Aldehyde dehydrogenase, dimeric NADP-preferring is an enzyme that in humans is encoded by the ''ALDH3A1'' gene.
Aldehyde dehydrogenases oxidize various aldehydes to the corresponding acids. They are involved in the detoxification of alcohol-deriv ...
. This LXA
4 activity has been demonstrated only in murine cells.
LXA
4 binds to and activates
estrogen receptor alpha
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex ...
. In this capacity, it mimics an estrogenic molecule to stimulate human
endometrial
The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...
epithelial cells ''in vitro'' and mouse uterine tissue ''in vivo''.
The actions of LXB
4 and 15-epi-LXB
4 have been far less well defined than those of their LXA
4 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
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
s, stimulate the recruitment of monocytes to inflammatory sites, enhance macrophage phagocytosis, and suppress the perception of inflammatory pain in rodents.
Animal model studies
Noninfectious inflammation
One or more of the lipoxins or their metabolically resistant analogs have been demonstrated to suppress, limit severity, and/or increase survival in a wide range of inflammatory and allergic diseases as evaluated in mouse and rat model studies. These studies include models of experimentally evoked:
Endometriosis
Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, f ...
,
colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification) ...
,
peritonitis
Peritonitis is inflammation of the localized or generalized peritoneum, the lining of the inner wall of the abdomen and cover of the abdominal organs. Symptoms may include severe pain, swelling of the abdomen, fever, or weight loss. One part or ...
;
pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
;
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
inflammation and
glomerulonephritis
Glomerulonephritis (GN) is a term used to refer to several kidney diseases (usually affecting both kidneys). Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the ...
; lung
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
, acid-induced lung injury,
cystic fibrosis
Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
,
pleurisy
Pleurisy, also known as pleuritis, is inflammation of the membranes that surround the lungs and line the chest cavity (pleurae). This can result in a sharp chest pain while breathing. Occasionally the pain may be a constant dull ache. Other sy ...
, brain inflammation and the inflammatory component of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
; vascular ischemia-reperfusion injuries to various organs including the heart and hind limb;
allograph
Allography, from the Greek for "other writing", has several meanings which all relate to how words and sounds are written down.
Authorship
An allograph may be the opposite of an autograph – i.e. a person's words or name (signature) written by so ...
Transplant rejection
Transplant rejection occurs when Organ transplant, transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between don ...
of heart, kidney, and
bone marrow
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
;
arthritis
Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
;
dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can v ...
;
periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
;
cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power ...
inflammation; and inflammation-based pain and
hyperalgesia
Hyperalgesia ( or ; 'hyper' from Greek ὑπέρ (huper, “over”), '-algesia' from Greek algos, ἄλγος (pain)) is an abnormally increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves and can ...
.
Infection-related inflammation
Lipoxins have protective effects in animal models of infection-based inflammation: a) LXA
4 and a LXA
4 analog decreased systemic inflammation and improved survival in rat models of
Gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
l
sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
;
b) 15-epi-LXA
4 suppressed the lung injury (i.e., shock lung or
Acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath (dyspnea), rapid breathing (tachypnea), and bluish skin colo ...
) caused by intraperitoneal injection of ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' in mice; c) 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
''Toxoplasma gondii'' () is an obligate intracellular parasitic protozoan (specifically an apicomplexan) that causes toxoplasmosis. Found worldwide, ''T. gondii'' is capable of infecting virtually all warm-blooded animals, but felids, such as d ...
'' and were rescued from these defects by LXA4
4;
d) LXA
4 restored macrophage function caused by
respiratory syncytial virus
Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a common, contagious virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. ...
in transgenic mice made deficient of lipoxin synthesis by ''Alox5'' gene deletion;
e) LXA
4 ameliorated infectious
periodontitis
Periodontal disease, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
in rabbit and porcine models.
f) 15-epi-LXA
4 decreased parasite blood levels, decrease cardiac inflammation, and increase survival in a mouse model of
Trypanosoma cruzi
''Trypanosoma cruzi'' is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood of ...
-induced
Chagas disease
Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by ''Trypanosoma cruzi''. It is spread mostly by insects in the subfamily ''Triatominae'', known as "kissing bugs". The symptoms change over the cou ...
;
f)' 15-epi-LXA
4 prolonged survival in a mouse model of ''
Plasmodium berghei
''Plasmodium berghei'' is a species in the genus ''Plasmodium'' subgenus ''Vinckeia''.
It is a protozoan parasite that causes malaria in certain rodents. Originally, isolated from thicket rats in Central Africa, ''P. berghei'' is one of four '' ...
''-induced cerebral malaria;
and g) LXA
4 shortens the duration of the allergic response to the parasitic infestation,
Angiostrongylus costaricensis
''Angiostrongylus costaricensis'' is a species of parasitic nematode and is the causative agent of abdominal angiostrongyliasis in humans. It occurs in Latin America and the Caribbean.
Hosts
Rodents are the normal definitive hosts, especially ...
.
However, lipoxins also have harmful effects in these models: aerosol infection with ''
Mycobacterium tuberculosis
''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...
'' in transgenic mice defective in ALOX5, which contributes to LX synthesis, exhibited far less severe inflammation and better survival than control mice;
and treatment of the transgenic mice with oral LXA
4 reversed the protective effect of ALOX5 deletion.
Human studies
Preclinical studies
LXs and epi-LXs have been detected in a 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.
LXA
4 inhibits the-bronchial contracting action of LTC4 and relaxes pre-contracted bronchi in asthmatic individuals.
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvirus ...
(KSHV) causes the malignant transformation of human cells and is responsible for
Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
and
primary effusion lymphoma
Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus (i.e. KSHV/HHV8). Plasmab ...
, two cancers which afflict in particular humans infected with
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
. Studies in human Kaposi sarcoma and primary effusion lymphoma cells find that: a) 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
4, apparently as a strategy to promote its latency and malignant transforming ability; b)' Kaposi sarcoma and primary effusion lymphoma cells express the ALX/FPR receptor; and c)' treatment of the latter cells with LXA
4 or 15-epi-LXA
4 reverses this pro-malignancy profile of pro-inflammatory signaling by an ALX/FPR-dependent mechanism. These studies suggest that the two LX's or their analogs should be tested in animal models to determine if the might be useful for treating the two human malignancies.
Clinical studies
In a
randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
, topical application of 15-epi-LXA4 or a comparatively stable analog of LXB4, 15''R/S''-methyl-LXB4, reduced the severity of
eczema
Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...
in a study of 60 infants.
Currently, BLXA4, a lipoxin analog, is in clinical trial phase 1 and currently recruiting volunteers for treating oral
gingivitis
Gingivitis is a non-destructive disease that causes inflammation of the gums. The most common form of gingivitis, and the most common form of periodontal disease overall, is in response to bacterial biofilms (also called plaque) that is attached ...
(see: ''Safety and Preliminary Efficacy of Lipoxin Analog BLXA4-ME Oral Rinse for the Treatment of Gingivitis (BLXA4)'' at https://clinicaltrials.gov/ct2/show/NCT02342691?term=Lipoxin&rank=3).
See also
*
Epi-lipoxins Epi-lipoxins are trihydroxy (i.e. containing 3 hydroxyl residues) metabolites of arachidonic acid. They are 15''R''-epimers of their lipoxin counterparts; that is, the epi-lipoxins, 15-epi-lipoxin A4 (15-epi-LxA4) and 15-epi-lipoxin B4 (15-epi-L ...
*
Specialized pro-resolving mediators
Specialized pro-resolving mediators (SPM, also termed specialized proresolving mediators) are a large and growing class of cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids (PUFA) by one or a combination of ...
*
15-Hydroxyeicosatetraenoic acid
15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S'' ...
References
External links
*
{{Aryl hydrocarbon receptor modulators
Eicosanoids