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Leukotrienes, Lipoxins and Related Eicosanoids



The oxygenated metabolites or oxylipins derived from arachidonic and related fatty acids are produced through a series of complex interrelated biosynthetic pathways often termed the 'eicosanoid cascade'. The prostanoids (prostaglandins, thromboxanes and prostacyclins) have distinctive ring structures in the centre of the molecule and are discussed on their own web page, as are the linear mono-hydroxyeicosatetraenes (HETE) and related lipids. Here, the di-substituted eicosanoids are described, including the leukotrienes, lipoxins, eoxins and hepoxilins, together with their manifold biological activities.

Certain types of reaction are common to both the synthesis of the pro-inflammatory lipid mediators such as the leukotrienes from essential fatty acids (EFA) and those with pro-resolution properties, such as the specialized pro-resolving mediators, i.e. the lipoxins, resolvins, protectins and maresins. First, there is an antarafacial hydrogen abstraction at the C3 position in a cis,cis-1,4-diene moieties. This is followed by a stereo-selective insertion of molecular oxygen to form a carbon-oxygen bond in a hydroperoxide intermediate, and then there is a second hydrogen abstraction with an intramolecular nucleophilic attack by the oxygen atom in this intermediate to produce an epoxide. The final step involves hydrolase-assisted nucleophilic addition of water to a cis-double bond in the epoxide intermediate (not illustrated).

Common reactions in the production of lipid mediators


1.   Leukotrienes

The term ‘leukotriene’ was coined because these important eicosanoids were first discovered by Samuelsson and colleagues in the white blood cells derived from bone marrow, i.e. the leukocytes, and they have three double bonds in conjugation (though they have four in total), resulting in specific absorbance peaks in their UV spectra (at 270, 280 and 290 nm). They are known to exhibit a wide range of biological activities, most of which involve some form of signalling function akin to that of short-lived paracrine reagents. However, their biological activities must be considered together with those of the lipoxins and other eicosanoids as the balance between them can be critical for health. Leukotrienes can be classified according to whether or not they are linked covalently to cysteine, and the structures and basic mechanism for biosynthesis of these oxylipins are described below.

5-Lipoxygenase - a key enzyme: The biosynthetic precursor of the leukotrienes is arachidonic acid released from phospholipids by the action of phospholipase A2, and this is acted upon by enzymes located at the endoplasmic reticulum (ER) or nuclear membrane, each of which has a high stereospecificity, starting with 5-lipoxygenase (5-LOX) (see our web page mono-hydroxyeicosatetraenes for a discussion of lipoxygenases in general). The 3- and 5-series leukotrienes are less studied and have 5,8,11-eicosatrienoic and 5,8,11,14,17-eicosapentaenoic acids, respectively, as the precursors. In humans, 5-LOX is expressed mainly in cells of myeloid origin (neutrophils, eosinophils, monocytes-macrophages and mast cells) and in foam cells of atherosclerotic tissue (in other cells, synthesis is blocked by DNA methylation). In resting cells, 5-LOX occurs either in the cytosol or in the nucleus as a soluble enzyme, depending on the cell type, but in response to cell activation, it co-migrates with phospholipase A2 to the endoplasmic reticulum and perinuclear membranes where the latter liberates arachidonic acid from phospholipids for metabolism. 5-LOX is similar in structure to other lipoxygenases and contains an α-helix catalytic domain that contains non-haeme iron and an N-terminal domain that binds to calcium and zwitterionic phosphatidylcholine in membranes (but not cationic phospholipids). These are essential for its activity. In contrast to the prostaglandins, an increase in free arachidonic acid alone is not sufficient to induce leukotriene synthesis. Little leukotriene synthesis occurs in resting cells, but it is stimulated by cellular events that raise the level of calcium ions, and the activity of the enzyme is regulated also by phosphorylation at three serine residues by specific kinases. The enzyme is regenerated after each catalytic cycle by either a mono-oxygenase or the LTA4 synthase mechanism.

Leukotriene biosynthesis: In the first step of a two-stage concerted reaction in leukotriene biosynthesis, 5‑LOX embedded in the membrane generates 5S‑hydroperoxy-6t,8c,11c,14c-eicosatetraenoic acid (5‑HPETE) by a dioxygenation reaction, i.e. the incorporation of one molecule of oxygen at the C-5 position. To function properly in the second step, 5-LOX requires the presence of two accessory proteins also embedded in the membrane - five‑lipoxygenase activating protein (FLAP) and coactosin-like protein (CLP). It is believed that FLAP exists as a trimer, which contains a binding pocket for arachidonic acid, from which the latter can interact with the 5-LOX catalytic domain and enable transfer to its active site. FLAP may also promote the functional coupling of phospholipase A2 (cPLA2) to 5-LOX at the membrane (both cPLA2 and 5-LOX are Ca2+ dependent). 5-HPETE can be released as such and reduced to 5S-hydroxy-eicosatetraenoic acid (5‑HETE), but with the aid of FLAP and CLP, 5-LOX is able to catalyse the transformation of 5-HPETE into 5,6-epoxy-7t,9t,11c,14c-eicosatetraenoic acid or leukotriene A4 (LTA4), which is the first of the leukotrienes. Although LTA4 is highly unstable with a half-life of only a few seconds at pH 7.4 in vitro, it is stabilized to some extent in cells by binding to albumin or other proteins that remove water from the immediate environment of the epoxide structure. It is a pivotal intermediate in the synthesis of other leukotrienes and of lipoxins (see below).

Biosynthesis of leukotrienes

The enzymic reactions leading to the dihydroxy acid LTB4 and the peptide-leukotrienes, especially LTC4, are much more important from a biological standpoint and their synthesis is controlled by the location of the enzymes for each product in specific types of cells in humans. Hydrolysis of LTA4 is catalysed by LTA4 hydrolase (LTA4H), a zinc-dependent metallo-protein, which has a dual activity as an aminopeptidase and is located mainly in neutrophils. Unlike most other enzymes involved in the 'leukotriene cascade', it is present in the cytosol of the cell so there must be some mechanism to ensure that it is close to the nuclear membrane where the other steps in the process occur. The product is the biologically active LTB4 or 5S,12R-dihydroxy-6,8,10,14-(Z,E,E,Z)-eicosatetraenoic acid. LTA4H has a high specificity for its substrate LTA4, and it undergoes suicide inactivation during catalysis. It has yet to be determined how such a labile molecule as LTA4 is transferred from 5-LOX to LTA4H and how the product LTB4 is transported to the plasma membrane for export.

Scottish thistleThe second pathway for LTA4 metabolism is prominent in cells expressing the enzyme LTC4 synthase or glutathione-S-transferase, which is found on the nuclear envelope of cells and adds the tripeptide glutathione (γ-glutamyl-cysteinyl glycine) to carbon-6 to yield peptido-leukotriene C4 (LTC4, 5(S),6(R)-S-glutathionyl-7,9,11,14-(E,E,Z,Z)-eicosatetraenoic acid, a 'cysteinyl leukotriene'; FLAP is again essential to the reaction. This enzyme is found in mainly in immune cells, such as mast cells, eosinophils and monocytes, but it is also present in platelets and epithelial cells. A subsequent reaction with γ-glutamyl-transpeptidase in the cytosol removes the glutamic acid residue to yield LTD4, which is acted upon by a dipeptidase to produce LTE4.

Trans-cellular biosynthesis. It has also become apparent that some of these transformations can occur in one cell type (donor cell) before the intermediate is passed to a second cell type (acceptor cell) to complete the conversion into the biologically active mediator, so mechanisms must exist to transport the eicosanoid intermediate between cells and across phospholipid membrane barriers. As some cell types do not have all the required enzyme systems for production of the full range of LTA4 metabolites, they can synthesise them by such trans-cellular mechanisms. For example, LTA4 synthesised in neutrophils is released to neighbouring acceptor cells such as erythrocytes or platelets that lack 5-LOX but possess the enzyme LTA4 hydrolase and are then able to produce leukotriene LTB4. Similarly, LTA4 generated and released from neutrophils is acted upon in acceptor cells such as platelets by the LTC4 synthase to produce LTC4. In spite of the high chemical reactivity of LTA4, these processes can be highly efficient and have the potential to generate high concentrations of cysteinyl-leukotrienes at the local level to affect organ function. Trans-cellular mechanisms are also important for the synthesis of lipoxins (see below).

Sulfido-conjugates that are related structurally to the cysteinyl-leukotrienes are now known to be produced from protectins, resolvins and maresins.

Catabolism. If LTA4 is not metabolized quickly, it can be transformed by non-enzymic hydrolysis of the epoxide ring into a variety of dihydroxy acids with relatively little biological activity (all four stereoisomers of LTB4). LTB4 is catabolized and its biological activity terminated in the liver by ω-oxidation carried out by a specific cytochrome P450 enzyme followed by β-oxidation from the ω-carboxyl position to produce 18-carboxy-dinor-LTB4. At this point, the pathway established for prostanoids and lipoxins (below) also operates. An alternative pathway in hepatocytes involves oxidation of the 12-hydroxyl group to produce biologically inactive 12-oxo metabolites. Catabolism and de-activation of LTC4 occurs by the sequential peptide cleavage reactions to form LTE4, which can then be subjected to ω-oxidation.

Leukotriene catabolism

Functions: As pro-inflammatory mediators, leukotrienes at concentrations in the low nanomolar range stimulate cellular responses that are quick in onset but do not last long, such as smooth muscle contraction, phagocyte chemotaxis, and increased vascular permeability, all of which are mediated via specific G‑protein coupled receptors. They are strongly implicated in immuno-metabolic disorders.

Scottish thistleLeukotriene B4 is one of the most potent chemotactic agents known and has an important function in the inflammatory process by its effect on leukocytes, mediated mainly via two cell surface G protein-coupled receptors, BLT1 and BLT2. BLT1 is the high-affinity receptor for LTB4 and is expressed primarily in leukocytes. The second leukotriene receptor BLT2 has a lower affinity for LTB4. It is expressed relatively ubiquitously in human tissues but is most active in epithelial cells of intestine and skin. Perhaps surprisingly, 12(S)‑hydroxyheptadeca-5Z,8E,10E–trienoic acid (12-HHT), a metabolite of prostaglandin H (PGH2), is a high affinity ligand. Relatively large amounts of this oxylipin are produced by activated platelets during skin injury, and activation of the BLT2 receptor on epidermal keratinocytes has a number of beneficial functions including accelerating skin wound healing by enhancing cell migration. Both receptors are seen as potential drug targets against inflammatory diseases.

LTB4 causes neutrophils to adhere to vascular endothelial cells and enhances the rate of migration of neutrophils into extra-vascular tissues, while triggering several functional responses important for host defence, including the secretion of lysosomal enzymes, the activation of NADPH oxidase activity, nitric oxide formation, and phagocytosis. Also, it activates such intracellular signalling events as the mobilization of calcium, activation of phospholipases, the production of diacylglycerols and phosphoinositides, and the release of either anti- or pro-inflammatory agents, depending on circumstances. It has beneficial properties in that it is involved in the elimination of pathogens, but hyperactivation can induce acute and chronic inflammation that result in various inflammatory diseases. For example, 5-lipoxygenase and LTB4 especially have been implicated in the chronic inflammation that is a part of the pathophysiology of asthma, rheumatoid arthritis, inflammatory bowel disease, metabolic disease and atherosclerosis, and they can promote the growth of certain cancers. The enzymes and receptors of the 5-LOX pathway are upregulated in adipose tissue, and LTB4 has a key role in adipose tissue inflammation. Also, it promotes liver steatosis and insulin resistance in muscle and adipose tissue, factors that are especially important in obesity.

In contrast, leukotriene B5 derived from eicosapentaenoic acid strongly inhibits the pro-inflammatory effects of LTB4. In relation to atherosclerotic plaques, it has been reported that the deleterious effects of leukotriene LTB4 resulting from an excessive inflammatory response are countered by the presence of specialized proresolving mediators, especially resolvin D1 (RvD1), suggesting a new therapeutic approach to promote plaque stability.

Formula of LTC4Leukotriene C4, together with LTD4 and LTE4 (the cysteinyl-leukotrienes, which jointly comprise the 'slow-acting substance of anaphylaxis', recognized but not identified in the 1930s), are known to exert a range of pro-inflammatory effects, including constriction of the airways and vascular smooth muscle, increasing plasma exudation and oedema, and enhanced mucus secretion. They are important mediators in asthma especially, but also in other inflammatory conditions, including atherosclerosis and myocardial infarction, cancer, and gastrointestinal, skin, and immune disorders, again exerting their effects through a number of receptors but mainly cysteinyl-leukotrienes type 1 (CysLT1R) and type 2 (CysLT2R) receptors at the plasma membrane and nuclear membrane. LTE4 has been reported to upregulate the prostaglandin synthase COX-2 through the PPARγ receptor in mast cells. LTD4 and LTE4 are overexpressed in several types of cancer and are considered to be tumorigenic. Up‑regulation of the expression of their receptors has been observed in several human cancers, so there is great interest currently in drugs that inhibit the effects of these lipids by functioning as agonists to their receptors. 5-Lipoxygenase inhibitors and antagonists to cysteinyl-leukotrienes receptors are both proving useful in treatment of asthma and rhinitis, and recent clinical evidence suggests that they may also be of value for the treatment of cardiovascular diseases. In addition, cysteinyl-leukotrienes have been implicated in a number of disorders of the central nervous system, including multiple sclerosis, Alzheimer's disease and Parkinson's disease.

While the general view is that leukotrienes produce harmful effects, especially in relation to the immune system and allergic diseases, such as asthma, there are suggestions that they may also be beneficial in that they stimulate the body’s innate immunity against pathogens, including bacterial, fungal and viral infections, by promoting the expression of mediators and receptors that are important for immune defence. For example, leukotriene B4 can trigger the release of antimicrobial agents.


2.   Lipoxins and Related Compounds

Lipoxins are trihydroxy-eicosatetraenoic acids, derived from arachidonic acid with the four double bonds in conjugation, which were the first lipid mediators to be discovered that were involved in the resolution phase of inflammation. Indeed, they are now considered to be specialized pro-resolving mediators (SPMs) (together with the resolvins, protectins and maresins, which are derived from the omega-3 family of polyunsaturated fatty acids). These molecules have structural similarities to the leukotrienes and appear to have some complementary biological activities. They are also formed by trans-cellular pathways, since few cell types have both of the required lipoxygenases.

There are at least three routes to the biosynthesis of lipoxins that differ among cell types. However, a common feature is the insertion of molecular oxygen at two sites in arachidonic acid by distinct lipoxygenases. For example as illustrated for the biosynthesis of the lipoxins designated A4 (LXA4) and B4 (LXB4) in human mucosal cells (airway epithelial cells, gastrointestinal tract and monocytes), the first step is the formation of 15S-hydroperoxy-5c,8c,11c,13t-eicosatetraenoic acid (15S-HPETE) by a 15-lipoxygenase (15-LOX - see the web page on hydroxy-eicosatetraenes (HETE)), which is activated by PGD2 and PGE2 to produce the lipoxin LXA4 and thereby suppress signals mediated by the leukotriene LTB4.

Biosynthesis of lipoxins

15S-HPETE or the reduced form 15S-HETE is then acted upon by a 5-lipoxygenase in neutrophils to form first an epoxy intermediate, i.e. 5S,6S-epoxy-15S-hydroxy-ETE and then, depending on the cell type, by specific hydrolases to form either 5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (LXA4), or to 5S,14R,15S-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid (LXB4). The stereochemistry of the 15S‑hydroxyl group is retained in both products. In addition to the unesterified form, the precursor 15-HETE is found esterified to phosphatidylinositol, and this may be a storage form in the membranes of inflammatory cells, to be released as required by stimulation of the phospholipase cPLA2α.

In a second mechanism in blood vessels, a trans-cellular interaction between leukocytes and platelets is involved via the same epoxy intermediate as in the first mechanism. The initial step is the action of a 5-lipoxygenase with the aid of FLAP in leukocytes to form leukotriene A4, which is secreted into the plasma and is available for reaction with a 12-lipoxygenase in platelets to form lipoxins (platelets are not able to produce lipoxins directly from arachidonate). Overall, these reactions also reduce leukotriene formation.

An important third mechanism has been discovered that produces lipoxins of different stereochemistry, i.e. the epi-lipoxins, sometimes termed the aspirin-triggered lipoxins (‘ATL’), as the reaction is initiated by aspirin and requires the cyclooxygenase COX-2 in the first step. As discussed in our web page on prostaglandins, COX-2 is induced in endothelial and epithelial cells in response to a variety of stimuli. The effect of aspirin is to acetylate the enzyme, switching its catalytic activity (and its chirality) from prostanoid biosynthesis to production of 15R-HETE rather than the S‑enantiomer. This is in turn converted to 5S,6S-epoxy-15R-hydroxy-ETE, as described above for lipoxins, by the action of the 5-lipoxygenase in leukocytes and thence to epi-lipoxins, i.e. epi-LXA4 (5S,6S,15S-trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid) and epi-LXB4 (5S,14R,15R-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid), the latter with 15R-stereochemistry. 15(R)-HETE produced by the action of a cytochrome P450 enzyme in the absence of aspirin can be converted to 15-epi-lipoxins also.

Biosynthesis of epi-lipoxins

In contrast to the trans-cellular pathway, both steps can occur in macrophages alone, i.e. in a single cell type. A complex sequence of reactions is involved beginning with activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, which results in accumulation of the cyclooxygenase-2-derived lipoxin precursor 15-HETE esterified to the membrane phospholipids, a reaction that can be enhanced by aspirin treatment. It may be stored in this inert form until required for anti-inflammatory purposes, when P2X7, a purinergic receptor for extracellular ATP, is activated with the result that efficient hydrolysis of the phospholipid-bound 15-HETE by group IVA cytosolic phospholipase A2 takes place followed by conversion of the unesterified 15-HETE to bioactive lipoxins by 5-lipoxygenase.

Catabolism. Lipoxins are deactivated by the actions of 15-hydroxyprostaglandin dehydrogenase and prostaglandin reductase with production of 13,14‑dihydro-15-hydroxy-LXA4 and eventually 15-oxo metabolites. The epi-lipoxins have a two-fold longer half-life than the lipoxins as they are catabolized less efficiently, possibly because of the distinctive 15R-stereochemistry.

Scottish thistleFunctions: Lipoxins were the first eicosanoids to be discovered with a role in the resolution of inflammation, i.e. they are 'switched on' to limit the effects of inflammation. Indeed together with the protectins, resolvins and maresins, they control the inflammatory response in such pathogenic conditions as asthma, periodontitis, arthritis, cardiovascular disorders, cancer, and gastrointestinal, periodontal, kidney and pulmonary diseases. They are also believed to exert neuro-protective effects. Thus, they have opposing effect to LTC4 and inhibit bronchial spasms. Like lipoxins, the aspirin-triggered epi-lipoxins have potent anti-inflammatory actions, and this may provide further explanation for the efficacy of aspirin as a drug. It not only inhibits the synthesis of pro-inflammatory mediators but also induces the synthesis of anti-inflammatory ones.

The distinctive lipoxin structures, which are conserved across species, seem to act at both temporally and spatially distinct sites from other eicosanoids involved in the inflammatory responses. In particular, LXA4 is produced endogenously and evokes protective effects mainly via interactions with a specific G-protein-coupled receptor complex (ALX or ALX/FPR2) and a nuclear transcription factor, although binding to other receptors has been reported. All of the observed reactions appear to be highly stereo-selective in terms of double bond geometry and the chirality of the hydroxyl groups. Indeed, the both the lipoxins and epilipoxins, together with the docosahexaenoic acid metabolite resolvin D1, function by activating this receptor.

In the initial phase of inflammation, prostaglandin PGE2 and other pro-inflammatory prostaglandins are produced. The signals that lead to the synthesis of such molecules in turn stimulate the transcription of enzymes required for the generation of lipoxins from arachidonate and the resolvins and protectins from fatty acids of the omega-3 family of fatty acids. By increasing their cytosolic calcium (Ca2+) levels, the lipoxins are believed to control the entry of neutrophils to sites of inflammation in affected organs and so function in promoting resolution of inflammation. They are chemo-attractants for monocytes, i.e. cells that are required for wound healing. They also inhibit the production and action of chemokines while simultaneously stimulating anti-inflammatory cytokines, effects that are mediated through various receptors. Likewise, by delaying the apoptosis of macrophages, lipoxins can promote resolution of inflammation. In effect, it appears that leukocytes are programmed to progress from pro- to anti-inflammatory responses, utilizing metabolites derived from both omega-6 and omega-3 fatty acids in the process. The possibilities for therapeutic intervention with lipoxins to reduce the adverse effects of inflammation in many different disease states are being actively explored in animal studies and with humans.

Lipoxins also have a regulatory role in the immune response to infection by parasitic pathogens, such as Toxoplasma gondii and Mycobacterium tuberculosis. LXB4 and epi-LXB4 are effective both by oral administration and topical application, and they appear to function via their own receptor, although this has yet to be identified.

It is now recognized that resolvin and lipoxin metabolism are intimately related. For example, resolvin D1 has been shown to decrease the ratio of proinflammatory leukotriene B4 to proresolving lipoxin A4 via a kinase signalling pathway by means of which the nuclear:cytoplasmic ratio of 5-lipoxygenase, the common enzyme in the biosynthesis of these two eicosanoids, is lowered. This shift in 5-LOX location dampens LTB4 production and enhances LXA4 production.


3.   Eoxins

Novel eicosanoids related to the cysteinyl-leukotrienes have been characterized as products of the 12/15-lipoxygenase (15-LOX-1) of human eosinophils and mast cells. The primary product of the lipoxygenase, 15-HPETE, is believed to react with the enzyme further to produce the 14,15‑epoxide, designated eoxin A4, and then by analogy with leukotriene biosynthesis this in turn reacts with glutathione to produce eoxin C4, and thence eoxin D4 (linked to Cys-Glc) and eoxin E4 (linked to Cys only).

Biosynthesis of eoxins

Functions: Like the cysteinyl-leukotrienes, the eoxins are potent pro-inflammatory agents. They have been implicated in inflammation of the airways in asthma patients, and in those with Hodgkin lymphoma, a malignant disorder with many characteristics of an inflammatory illness. Ethanolamides of EXC4 and EXD4, termed 'eoxamides' and analogues of anandamide, are produced in human cell preparations in vitro.


4.  Hepoxilins

Hepoxilins are short-lived monohydroxy-epoxy eicosanoids produced in a number of organs or cell types, but especially the epidermis in humans, and derived mainly from the product of one of two divergent pathways involving the action of the 12-lipoxygenase, of which the spinal eLOX3 isoform is especially important, on unesterified arachidonic acid, i.e. to produce 12S-hydroperoxy-5c,8c,10t,14c-eicosatetraenoic acid (12S‑HPETE). This can either be reduced to the hydroxy compound (12S-HETE) or it can be acted upon by a hepoxilin synthase (isomerase), which effects isomerization of the hydroperoxide group to produce an epoxide. The relative rates of the two pathways are controlled by the reducing potential of the cell.

Structural formulae of hepoxilins

Hepoxilins contain both hydroxyl and epoxy groups, the latter across the C11-C12 double bond, and unlike the leukotrienes and lipoxins, none of the double bonds are in conjugation. Two have been characterized, i.e. 8(S/R)-hydroxy-11S,12S-trans-epoxyeicosa-5c,9t14c-trienoic acid (hepoxilin A3 or HXA3) and 10(S/R)‑hydroxy-11S,12S-trans-epoxyeicosa-5c,9c14c-trienoic acid (hepoxilin B3 or HXB3). Only HXA3 is known to be biologically active. The epoxide ring is labile and can be opened by an epoxide hydrolase to yield trihydroxy metabolites termed ‘trioxilins’, which may also have some biological activity.

Analogous compounds derived from eicosapentaenoic and docosahexaenoic acids have been described. In skin, the epidermal lipoxygenase 12R-LOX generates the fatty acid hydroperoxide R-HPODE from linoleate before eLOX3 acting as a hydroperoxide isomerase produces hepoxilin-like compounds, which are believed to induce changes to the complex structural ceramides in this tissue by promoting linkage of the ω-hydroxyl group to proteins (see our web page on skin ceramides for further discussion).

Formation of hepoxilin-like compounds from linoleate in epidermis

Functions: Hepoxilins have pro-inflammatory properties in the skin, but anti-inflammatory in neutrophils. Most of the observed activities are associated with mobilization of calcium and potassium within cells or across membranes. In addition, hepoxilin A3 is now known to be an important regulator of mucosal inflammation in response to infection by bacterial pathogens, such as that responsible for Lyme disease. Although lipoxygenase activity in brain tissues tends to be low, there is significant biosynthesis of hepoxilins in the pineal gland, which may be involved in the regulation of melatonin production. It contributes to increased sensitivity to pain during inflammation by activation of TRPV1 and TRPA1 receptors. Stable synthetic analogues of hepoxilins are effective in animal models of lung fibrosis, cancer, thrombosis and diabetes.


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Lipid listings Credits/disclaimer Updated: October 19th, 2018 Author: William W. Christie LipidWeb icon