5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Inflammation

Type I hypersensitivity is an immediate immune reaction that involves IgE-mediated activation of mast cells. Activated mast cells release chemical mediators, such as histamine and lipid mediators, which cause allergic reactions. Recent developments in detection devices have revealed that mast cells simultaneously release a wide variety of lipid mediators. Mounting evidence has revealed that mast cell-derived mediators exert both pro- and anti-inflammatory functions and positively and negatively regulate the development of allergic inflammation. This review presents the roles of major lipid mediators released from mast cells. Author believes this review will be helpful for a better understanding of the pathogenesis of allergic diseases and provide a new strategy for the diagnosis and treatment of allergic reactions.

Topics: Fatty Acids, Unsaturated; Histamine Release; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity, Immediate; Immunoglobulin E; Inflammation; Leukotriene B4; Leukotriene C4; Lipid Metabolism; Mast Cells; Prostaglandin D2

Topics: Animals; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Neutrophils; Phagocytes; Protein Kinase C; Second Messenger Systems; Superoxides

To identify biomarkers of orange juice (OJ) consumption containing different doses of polyphenols and to determine its impact on oxidative stress and inflammation using an untargeted metabolomics analysis.. Thirty subjects aged 22-63 years from the BIONAOS study consumed a normal-polyphenol OJ (NPJ) or a high-polyphenol OJ (HPJ) (299 or 745 mg/L, respectively) for 12 weeks in a randomized, parallel, double-blind study. UHPLC-MS, univariate and multivariate statistical analysis and ROC curves were used to design biomarkers of consumption in serum. We propose betonicine, stachydrine, methyl glucopyranoside (alpha+beta), dihydroferulic acid and galactonate as a new metabolic signature to distinguish the intake of OJ with a different polyphenol content. Changes in metabolites related to OJ, oxidative stress and inflammation were observed. After HPJ consumption, the serum levels of hydroxyoctadecadienoic acid (9-HODE+13-HODE) and dihydroxyoctadecanoic acid (12,13-DiHOME and 9,10-DiHOME) decreased, whereas levels of 12-hydroxyeicosatetraenoic acid (12-HETE) increased. 5-HETE increased after the NPJ intervention exclusively.. We designed a new panel of biomarkers to differentiate the intake of OJs containing different doses of polyphenols. On the other hand, the consumption of an OJ with a high content of flavanones improved oxidative stress and inflammatory biomarkers.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Biomarkers; Citrus sinensis; Female; Fruit and Vegetable Juices; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Male; Metabolomics; Middle Aged; Oxidative Stress; Polyphenols; Proline; Tandem Mass Spectrometry; Young Adult

Topics: Antioxidants; Glutathione; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Metal Nanoparticles; Mitochondria; Oxidative Stress; Silver; THP-1 Cells; Titanium; Zinc Oxide

The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A

Topics: Animals; Cell Movement; Cell Nucleus; Cell Proliferation; Ceramides; Collagen; Cytoplasm; Cytosol; Dinoprostone; Eicosanoids; Fibroblasts; Genotype; Group IV Phospholipases A2; Hydroxyeicosatetraenoic Acids; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Phenotype; Skin; Tensile Strength; Thromboxane B2; Wound Healing

Topics: Arachidonate 15-Lipoxygenase; Arachidonic Acids; Cyclooxygenase 2; Deuterium; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Kinetics

Oxylipids are oxygenated polyunsaturated fatty acid (PUFA) metabolites that are responsible for the onset and resolution of the inflammatory response. Enzymatic oxygenation through the lipoxygenase (LOX) or cytochrome P450 (CYP) pathways can form oxylipids that have either proinflammatory or proresolving functions depending on the type of PUFA substrate and degree of metabolism. The objective of this study was to determine how PUFA substrates and their corresponding oxylipids are associated with obesity.. Plasma non-esterified FA and oxylipids were isolated from 123 Caucasian males using solid phase extraction and quantified using high performance liquid chromatography-tandem mass spectrometry. Statistical analyses included linear regressions and polytomous logistic regressions, and the responses were body mass index (BMI) and waist circumference (WC), and serum leptin, total adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-peptide. Models were adjusted for age and smoking, and p-values were corrected for false discovery per Benjamini-Hochberg and Bonferroni.. We report that BMI, WC, and several serum cytokines were highly associated arachidonic acid (ARA)-derived hydroxyeicosatetraenoic acids (HETEs), and vicinal diols (i.e., alcohols on adjacent carbon atoms) derived from several PUFAs. There was a significant linear relationship between BMI, WC, and serum leptin, and ARA-derived 5-, 11-, and 15-HETE. Specifically, BMI and WC were positively associated with proinflammatory 5- and 11-hydroxyeicosatetraenoic acid (HETE), even after normalization to ARA concentrations and false discovery p-value correction. Individuals with 5-HETE concentrations >5.01nmol/L or 11-HETE concentrations and >0.89nmol/L were over 5 times more likely to be obese compared to those with ≤1.86nmol/L and ≤0.39nmol/L, respectively. Vicinal diols from linoleic, eicosapentaenoic, and docosahexaenoic acid were inversely associated with obesity. Across all statistical tests, vicinal diols were inversely associated with obesity whether normalized to parent PUFA concentrations or normalized to precursor epoxides. Interestingly, the proinflammatory cytokines IL-6 and TNF-α were not associated with any oxylipids. Since 5-HETE is a 5LOX product, 11-HETE is marker of lipid peroxidation, and vicinal diols are formed through soluble epoxide hydrolase (sEH) metabolism of CYP epoxygenated PUFAs, therefore, these results indicate that obesity is likely associated with altered metabolism with distinct oxygenating pathways. Taken together, our results indicate that obesity is associated with specific oxylipids indicative of altered PUFA metabolism through several pathways (i.e., LOX, reactive oxygen species, and sEH and CYP epoxygenase), rather than attributed solely to altered dietary PUFA intake.

Topics: Aged; Arachidonic Acid; Biomarkers; Cross-Sectional Studies; Cytochrome P-450 Enzyme System; Fatty Acids, Unsaturated; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Lipoxygenase; Male; Metabolic Networks and Pathways; Middle Aged; Obesity; White People

Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Aspirin; Benzoates; Blood Pressure; Dose-Response Relationship, Drug; Enzyme Activation; Epoxide Hydrolases; Gene Expression Regulation, Enzymologic; Hydroxyeicosatetraenoic Acids; Indoles; Inflammation; Lipopolysaccharides; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Urea

Monocytes/macrophages committed to death by peroxynitrite nevertheless survive with a signaling response promoting Bad phosphorylation, as well as its cytosolic localization, via upstream activation of cytosolic phospholipase A(2), 5-lipoxygenase, and protein kinase C alpha. We now report evidence for an alternative mechanism converging in Bad phosphorylation when the expression/activity of the above enzymes are suppressed. Under these conditions, also associated with peroxynitrite-dependent severe inhibition of Akt, an additional Bad kinase, Bad dephosphorylation promoted its accumulation in the mitochondria and a prompt lethal response. PGE(2) prevented toxicity via EP(2) receptor-mediated protein kinase A-dependent Bad phosphorylation. This notion was established in U937 cells by the following criteria: 1) there was a strong correlation between survival and cAMP accumulation, both in the absence and presence of phosphodiesterase inhibitors; 2) direct activation of adenylyl cyclase afforded cytoprotection; and 3) PGE(2) promoted loss of mitochondrial Bad and cytoprotection, mimicked by EP(2) receptor agonists, and prevented by EP(2) receptor antagonists or protein kinase A inhibitors. Finally, selected experiments performed in human monocytes/macrophages and in rat peritoneal macrophages indicated that the above cytoprotective pathway is a general response of cells belonging to the monocyte/macrophage lineage to both exogenous and endogenous peroxynitrite. The notion that two different pathways mediated by downstream products of arachidonic acid metabolism converge in Bad phosphorylation emphasizes the relevance of this strategy for the regulation of macrophage survival to peroxynitrite at the inflammatory sites.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; bcl-Associated Death Protein; Cell Death; Cell Survival; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprostone; Enzyme Activation; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Macrophages, Peritoneal; Mitochondrial Proteins; Monocytes; Peroxynitrous Acid; Phospholipase A2 Inhibitors; Phospholipases A2; Phosphorylation; Protein Kinase C-alpha; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; U937 Cells

Sebaleic acid (5,8-octadecadienoic acid) is the major polyunsaturated fatty acid in human sebum and skin surface lipids. The objective of the present study was to investigate the metabolism of this fatty acid by human neutrophils and to determine whether its metabolites are biologically active. Neutrophils converted sebaleic acid to four major products, which were identified by their chromatographic properties, UV absorbance, and mass spectra as 5-hydroxy-(6E,8Z)-octadecadienoic acid (5-HODE), 5-oxo-(6E,8Z)-octadecadienoic acid (5-oxo-ODE), 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid, and 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid. The identities of these metabolites were confirmed by comparison of their properties with those of authentic chemically synthesized standards. Both neutrophils and human keratinocytes converted 5-HODE to 5-oxo-ODE. This reaction was stimulated in neutrophils by phorbol myristate acetate and in keratinocytes by oxidative stress (t-butyl-hydroperoxide). Both treatments dramatically elevated intracellular levels of NADP(+), the cofactor required by 5-hydroxyeicosanoid dehydrogenase. In keratinocytes, this was accompanied by a rapid increase in intracellular GSSG levels, consistent with the involvement of glutathione peroxidase. 5-Oxo-ODE stimulated calcium mobilization in human neutrophils and induced desensitization to 5-oxo-6,8,11,14-eicosatetraenoic acid but not leukotriene B(4), indicating that this effect was mediated by the OXE receptor. 5-Oxo-ODE and its 8-trans isomer were equipotent with 5-oxo-6,8,11,14-eicosatetraenoic acid in stimulating actin polymerization and chemotaxis in human neutrophils, whereas 5-HODE, 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid, and 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid were much less active. We conclude that neutrophil 5-lipoxygenase converts sebaleic acid to 5-HODE, which can be further metabolized to 5-oxo-ODE by 5-hydroxyeicosanoid dehydrogenase in neutrophils and keratinocytes. Because of its chemoattractant properties, sebum-derived 5-oxo-ODE could be involved in neutrophil infiltration in inflammatory skin diseases.

Topics: Calcium; Chemotactic Factors; Chemotaxis; Fatty Acids, Unsaturated; Granulocytes; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Keratinocytes; Linoleic Acids; Models, Chemical; NADP; Neutrophils; Sebum; Skin

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and alpha-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Body Weight; Cyclooxygenase 2; Dinoprostone; Eflornithine; Esophageal Neoplasms; Esophagus; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Immunoenzyme Techniques; In Situ Hybridization; Inflammation; Isoenzymes; Leukotriene B4; Male; Masoprocol; Mass Spectrometry; Neoplasms; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sulindac; Time Factors

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B(4) possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.

Topics: Animals; Capsaicin; Cell Line; Cells, Cultured; Dinoprostone; Eicosanoids; Ganglia, Spinal; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Ion Channel Gating; Leukotriene B4; Leukotrienes; Ligands; Lipid Peroxides; Lipoxygenase; Molecular Structure; Neurons, Afferent; Prostaglandin D2; Prostaglandin H2; Prostaglandins H; Rats; Receptors, Drug; Structure-Activity Relationship

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Asthma; Biomarkers; Blood Chemical Analysis; Case-Control Studies; Chromatography, High Pressure Liquid; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Inflammation Mediators; Reference Standards; Rhinitis, Allergic, Seasonal

Sch 40120 (10-(3-chlorophenyl)-6,8,9,10-tetrahydrobenzo[b] [1,8]naphthyridin-5(7H)-one) is an inhibitor of the 5-lipoxygenase enzyme in rat neutrophils, human neutrophils and the the MC9 murine mast cell clone with IC50 values of 8, 4 and 7 microM, respectively. The drug was examined for its effects on acute inflammatory responses in the paw and pleural cavity of rats. The drug suppressed paw inflammation triggered by a reverse passive Arthus reaction or a subplantar injection of the polysaccharide carrageenan with p.o. ED50 values of 0.2 and 1.5 mg/kg, respectively. In reverse passive Arthus reaction and carrageenan pleurisy models, Sch 40120 was found to suppress both the cellular and fluid components of the acute inflammation. The p.o. ED50 values for inhibition of cells and fluid in pleurisy models were in the range of 0.1 to 0.7 mg/kg. When applied locally to the ears of mice, the drug blocked an arachidonic acid-induced and leukotriene-mediated ear inflammation with an ED50 of 0.072 mg/ear. These findings suggest that Sch 40120 is a potent anti-inflammatory agent that may be particularly useful in the treatment of inflammatory diseases such as psoriasis in which leukotrienes appear to be major mediators of the pathological symptoms that characterize the disease state.

Topics: Acute Disease; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arthus Reaction; Cyclooxygenase Inhibitors; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Inflammation; Lipoxygenase Inhibitors; Naphthyridines; Neutrophils

Topics: Adult; Arachidonate 5-Lipoxygenase; Gastric Mucosa; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotrienes; Male; Middle Aged; Oxygen; Radioimmunoassay; Regression Analysis; Stomach Ulcer

Topics: Adapalene; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arachidonic Acids; Carrageenan; Cell Differentiation; Chemotaxis, Leukocyte; Croton Oil; Erythema; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Inflammation; Lipoxygenase; Luminescent Measurements; Mice; Naphthalenes; Neutrophils; Passive Cutaneous Anaphylaxis; Rabbits; Rats; Ultraviolet Rays

We investigated the role of various E. coli strains that expressed different adhesins and/or generated haemolysin with regard to the induction of inflammatory mediators, e.g. histamine release from rat mast cells as well as the chemiluminescence response and the release of lipoxygenase transformation products from human polymorphonuclear neutrophils. Our data show that the degree of haemagglutination did not parallel the induction of the chemiluminescence response. Haemolysin-negative bacteria with different adhesins induced more 5-hydroxyeicosatetraenoic acid as compared to haemolysin-positive bacteria, which generated more leukotriene B4 as compared to 5-hydroxyeicosatetraenoic acid. Among the leukotrienes, more leukotriene B4 as compared to leukotriene C4 was released from peripheral leucocytes. Studies with rat mast cells showed that histamine release was dependent on the haemolysin activity expressed by washed bacteria or present within the bacterial culture supernatant. Histamine release was markedly diminished when haemolysin activity decayed. Several haemolysin-negative bacteria with defined adhesins also released histamine, suggesting that, in addition to haemolysin, other factors contribute to mediator release. Thus, various properties of bacteria (e.g. adhesins, haemolysin) may participate to varying degrees in the induction of inflammatory mediators, e.g. oxygen radicals, lipoxygenase transformation products, leucotrienes and histamine.

Topics: Adhesins, Escherichia coli; Animals; Bacterial Proteins; Escherichia coli; Hemagglutination; Hemolysin Proteins; Histamine Release; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotriene B4; Luminescent Measurements; Mast Cells; Neutrophils; Rats; SRS-A

It was shown that 15-hydroxyeicosatetraenoic acid (15-HETE) but not 15-H(P)ETE or 5-HETE is a potent agonist for secretion of glycoprotein-containing mucus from the in vivo canine trachea. Given by aerosol into the lungs or by intra-arterial injection into the trachea, 15 HETE also caused the chemotaxis of inflammatory cells into the lumen of the airways. Accompanying this inflammatory cell infiltrate was an increase (183%, p less than 0.05) of expiration of fluid in the partially saturated air coming from the lung. The levels of 15-HETE extracted from tracheal mucus correlated well with hillocks and weight of secreted mucus found in the mucus after hypoxia or after arachidonic acid loading. Indomethacin and atropine blocked the mucus secretagogue effect of 15-HETE in the trachea. Indomethacin and U-52, 412 (a 15-lipoxygenase inhibitor) pretreatment abolished a portion of the 15-HETE-induced enhancement of mucus weight and 15-HETE level in the secretion.

Topics: Aerosols; Animals; Arachidonic Acid; Arachidonic Acids; Body Fluids; Cell Movement; Chemotaxis; Dogs; Hydroxyeicosatetraenoic Acids; Hypoxia; Inflammation; Leukotrienes; Lipid Peroxides; Lipoxygenase Inhibitors; Mucus; Respiration; Respiratory System; Respiratory Tract Diseases; Trachea

The leukocyte lipoxygenase products LTB4 and 5-HETE elicit human neutrophil and eosinophil chemotactic responses in vitro and in vivo (Fig. 4), and are present at elevated concentrations in the lesions of some human inflammatory diseases, such as rheumatoid arthritis and the spondyloarthritides. The chemotactic potency of LTB4 is similar to that of the minor fragment of the fifth component of human complement, termed C5a, and is 30- to 300-fold greater than that of 5-HETE and of other natural DHETE isomers. Human neutrophils possess distinct subsets of chemotactic factor receptors that are specific for LTB4 and for 5-HETE, as demonstrated by the selective competitive inhibition of the chemotactic responses to the parent stimuli by acetyl LTB4 and 5-HETE methyl ester, respectively, and by the failure of the lipid chemotactic factors to bind to isolated membrane protein constituents of the human neutrophil receptors for chemotactic formyl-methionyl peptides. LTB4 and 5-HETE also elicit human neutrophil and eosinophil chemokinesis, stimulate the uptake of calcium and D-glucose, and enhance the expression of C3b receptors on the leukocytes; however, they exert only a minimal effect on superoxide generation and lysosomal enzyme release. LTB4, but not 5-HETE, stimulates the release of calcium from previously unexchangeable intraneutrophil pools, as has been described for potent peptide chemotactic factors. Although far less potent than LTC4 and LTD4, LTB4 constricts peripheral airways, enhances mucous secretion in the airways of the lung, and dilates and enhances the permeability of the microvasculature in skin and other organs (Fig. 4). A variety of leukocyte functions, including chemotaxis, D-glucose uptake, and lysosomal enzyme release, are impaired in association with the depletion of endogenous lipoxygenase products. Exogenous 5-HETE reverses some of the functional deficits of HETE-depleted leukocytes. Inhibition of leukocyte lipoxygenase activity also suppresses the intracellular content of hydroperoxyeicosatetraenoic acids and of novel polar metabolites of arachidonic acid that may be critical to the activation of human neutrophils and eosinophils. Thus LTB4 and the less potent 5-HETE are active extracellular mediators of the leukocytic components of hypersensitivity and inflammation and may also serve an important role as intracellular mediators of leukocyte function.

Topics: Arachidonate Lipoxygenases; Arachidonic Acids; Chemotaxis; Eosinophils; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase; Neutrophils; Oligopeptides; Receptors, Cell Surface; Receptors, Formyl Peptide

Topics: Animals; Arachidonic Acids; Autacoids; Basophils; Bronchi; Chemical Phenomena; Chemistry; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity; In Vitro Techniques; Inflammation; Mast Cells; Mice; Muscle Contraction; Muscle, Smooth; Rats; SRS-A