Lipoxin
Encyclopedia
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
mediators. Lipoxins are short lived endogenously produced nonclassic eicosanoid
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...
s whose appearance in inflammation signals the resolution of inflammation.
They are abbreviated as LX, an acronym for lipoxygenase
Lipoxygenase
Lipoxygenases are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:...
(LO) interaction products.
At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4).
History
Lipoxins were first described by Serhan, Hamberg andSamuelsson
Bengt I. Samuelsson
-External links:**...
in 1984. They reported that the lipoxins
stimulated superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
anion (O2−) generation and degranulation
Degranulation
Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells...
at submicromolar concentrations—as potent as LTB4
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
.
Biosynthesis
Lipoxins are derived enzymatically from arachidonic acidArachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
, an ω-6 fatty acid
Omega-6 fatty acid
n−6 fatty acids are a family of unsaturated fatty acids that have in common a final carbon–carbon double bond in the n−6 position, that is, the sixth bond, counting from the methyl end.The biological effects of the n−6 fatty acids are largely mediated by their conversion to n-6 eicosanoids...
. An analogous class, the resolvins
Resolvins
Resolvins are compounds that are made by the human body from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid . They are produced by the COX-2 pathway especially in the presence of aspirin...
, are derived from EPA
Eicosapentaenoic acid
Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5. It also has the trivial name timnodonic acid...
and DHA
Docosahexaenoic acid
Docosahexaenoic acid is an omega-3 fatty acid that is a primary structural component of the human brain and retina. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end...
, ω-3 fatty acids
Omega-3 fatty acid
N−3 fatty acids are essential unsaturated fatty acids with a double bond starting after the third carbon atom from the end of the carbon chain....
.
Another analogous class, the epi-lipoxin
Epi-lipoxin
Epi-lipoxins are the 5R-epimers of lipoxins.These nonclassic eicosanoids are formed in vivo, in the presence of aspirin. They play a counter-regulatory role in inflammation, serving as a stop signal....
s, are formed by non-enzymatic peroxidation
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
.
Biological activity
Lipoxins, as well as certain peptides, are high affinity ligands for the lipoxin A4 receptor (LXA4R), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the LXA4R inhibits chemotaxisChemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
, transmigration, superoxide generation and NF-κB activation.
Conversely, peptide signaling through the same receptor, in vitro, has been shown to stimulate chemotaxis of polymorphonuclear cells (PMNs) and calcium mobilization. The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase protein
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...
s, bacterial peptides, HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
envelope proteins and neurotoxic peptides.
Similarly to the leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
s, LXA4 will form the cysteinyl-lipoxins
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
LXC4, LXD4 and LXE4. At subnanomolar concentrations, LXA4 and LXB4 inhibit leukotriene-stimulated interactions of human neutrophil
Neutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
s and endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
cells.
Lipoxins are high affinity antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
to the cysteinyl leukotriene receptor type 1 (CysLT1) to which several leukotrienes (LTC4, LTD4 and LTE4) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug montelukast
Montelukast
Montelukast is a leukotriene receptor antagonist used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally...
(Singulair).
In resolution
During inflammation, cells die by apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. As part of resolution, lipoxins signal macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s to the remains of these cells (phagocytosis).
During the acute inflammatory process
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, the proinflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s such as IFN-γ
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins and IL-4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
, which promote the resolution phase of inflammation.