leukotriene-a4 and Inflammation

Topics: Animals; Arachidonate 5-Lipoxygenase; Aspirin; Cell Communication; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Leukotriene A4; Lipoxins; Prostaglandins

Metabolites of arachidonic acid have important regulatory functions within several areas of concern to the otolaryngologist. Prostaglandins, composing one group, are involved in smooth-muscle contraction, regulation of renal glomerular blood flow, and in the modulation of immune and allergic responses, inflammation, fever, pain, and tumor growth. A second group, the leukotrienes, may be even more important than prostaglandins in allergy and inflammation. The elusive slow-reacting substance of anaphylaxis belongs in this group. Two other metabolites, thromboxane and prostacyclin, seem to be critical in hemostasis and the metastatic spread of tumors.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Hypersensitivity; Indomethacin; Inflammation; Leukotriene A4; Lipoxygenase; Neoplasms; Phospholipases; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxanes

Leukotrienes are a new family of metabolites of arachidonic acid produced by a C-5 lipoxygenase. As shown on figure 1, leukotriene A4, the key compound in their biosynthesis could either be hydrolysed to form leukotriene B4 or combine with glutathione to form leukotriene C4. Removal of glycine from the glutathione substituent or removal of glycine and gamma-glutamic acid yields the leukotriene D4 and E4 respectively. Leukotriene C4, D4 and E4 are the main bioactive components of the long elusive "Slow Reacting Substance of Anaphylaxis" (SRS-A). They induce powerful contractions of lung parenchyma strips and trachea in vitro (fig. 2) as well as powerful bronchoconstriction in vivo. They also favor mucus production from airways and slow its transport. Leukotrienes exhibit vasoconstrictor activity both on large blood vessels and on the microcirculation and induce marked increases in blood pressure followed by long lasting slight decreases (fig. 3). Injections of leukotriene B4 produce erythema, neutrophil migration and, in association with prostaglandin E2, increase vascular permeability and cause oedema. Leukotriene B4 is a powerful chemoattractant for polymorphonuclear leukocytes, stimulates cellular aggregation, degranulation and the release of lysosomal enzymes. It is also involved in the modulation of the immune response by inducing the formation of suppressor and of cytotoxic cells. The pharmacological actions of leukotriene B4 are mediated by very specific receptors while the actions of leukotriene C4, D4 and E4 are mediated by another type of receptors which are blocked by the selective SRS-A antagonist FPL-55712. The actions of leukotrienes depend partly upon the formation of prostaglandins and thromboxanes in the guinea-pig lungs while in man, their actions appear mostly a direct myotropic effect (fig. 4). Leukotriene formation has been stimulated in lungs and in various leukocyte populations by inflammatory or hypersensitivity reactions and by non specific stimuli such as the ionophore A-23187 and the C5a-anaphylatoxin. Inhibitors of lipoxygenases and corticosteroids could inhibit their release while non-steroid anti-inflammatory drugs such as aspirin may potentiate their formation by rechanneling their substrate from the cyclooxygenase cascade (fig. 5). The activity and potency of leukotrienes, their putative role in various important diseases as well as the explanations which they may give to old problems are good reasons to justify our interest

Topics: Animals; Arachidonic Acids; Cardiovascular System; Humans; Inflammation; Leukocytes; Leukotriene A4; Leukotriene B4; Lung; SRS-A

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Biotransformation; Cyclooxygenase Inhibitors; Gastric Mucosa; Hemostasis; Humans; Inflammation; Leukotriene A4; Leukotriene B4; Muscle, Smooth; Neutrophils; Prostaglandins; SRS-A; Thromboxanes

Immunological and non-immunological injury induce as a result of the action of the enzyme lipoxygenase the release of a series of arachidonic acid metabolites known as leukotrienes. The leukotrienes play an important role in allergic and inflammatory disease. Leukotrienes C4, D4 and E4 which recently have been recognized as constituents of the allergic mediator slow reacting substance of anaphylaxis (SRS-A) induce powerful bronchoconstriction, plasma exudation and weal and flare responses. Leukotriene B4 is involved in the regulation of chemotaxis, chemokinesis and other aspects of both cellular and vascular inflammation. The development of specific lipoxygenase inhibitors may lead to a new class of drugs for the treatment of bronchial asthma and chronic inflammatory diseases.

Topics: Arachidonic Acids; Asthma; Biotransformation; Chemotaxis, Leukocyte; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lipoxygenase; Lipoxygenase Inhibitors; Neutrophils; SRS-A

Topics: Animals; Arachidonic Acids; Autacoids; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Molecular Conformation; Neutrophils; Rats; SRS-A; Structure-Activity Relationship; Terminology as Topic

Adjunctive dexamethasone saves lives in the treatment of tuberculous meningitis but this response is influenced by the patient's LTA4H genotype. Despite less certain benefit, adjunctive dexamethasone is also frequently used in the treatment of pyogenic bacterial meningitis, but the influence of LTA4H genotype on outcomes has not been previously investigated. We genotyped the LTA4H promoter region SNP (rs17525495) in 390 bacterial meningitis patients and 751 population controls. rs17525495 was associated with susceptibility to bacteriologically confirmed bacterial meningitis (P = 0.01, OR 1.27 95% confidence interval [CI] 1.05-1.54) but did not influence clinical presentation, disease severity or survival following dexamethasone treatment.

Topics: Adult; Dexamethasone; Disease Progression; Epoxide Hydrolases; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Inflammation; Leukotriene A4; Male; Middle Aged; Polymorphism, Single Nucleotide; Tuberculosis, Meningeal

Patients with diabetes present a persistent inflammatory process, leading to impaired wound healing. Since nonhealing diabetic wound management shows limited results, the introduction of advanced therapies targeting and correcting the inflammatory status of macrophages in chronic wounds could be an effective therapeutic strategy to stop the sustained inflammation and to return to a healing state. In an excisional skin injury in a diet-induced diabetic murine model, we demonstrate that topical administration of low-dose aspirin (36 μg/wound/day) improves cutaneous wound healing by increasing wound closure through the promotion of the inflammation resolution program of macrophages. This treatment increased efferocytosis of wound macrophages from aspirin-treated diabetic mice compared with untreated diabetic mice. We also show that aspirin treatment of high-fat-fed mice oriented the phenotype of wound macrophages toward an anti-inflammatory and proresolutive profile characterized by a decrease of LTB4 production. The use of diabetic mice deficient for 5-LOX or 12/15-LOX demonstrated that these two enzymes of acid arachidonic metabolism are essential for the beneficial effect of aspirin on wound healing. Thus, aspirin treatment modified the balance between pro- and anti-inflammatory eicosanoids by promoting the synthesis of proresolving LXA4 through 5-LOX, LTA4, 12/15-LOX signaling. In conclusion, the restoration of an anti-inflammatory and proresolutive phenotype of wound macrophages by the topical administration of low-dose aspirin represents a promising therapeutic approach in chronic wounds.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Aspirin; Diabetes Mellitus, Experimental; Inflammation; Leukotriene A4; Leukotriene B4; Lipoxins; Macrophages; Mice; Phenotype; Skin; Wound Healing

Neutrophils (PMNs) are key mediators of inflammatory processes throughout the body. In this study, we investigated the role of acrolein, a highly reactive aldehyde that is ubiquitously present in the environment and produced endogenously at sites of inflammation, in mediating PMN-mediated degradation of collagen facilitating proline-glycine-proline (PGP) production. We treated peripheral blood neutrophils with acrolein and analyzed cell supernatants and lysates for matrix metalloproteinase-9 (MMP-9) and prolyl endopeptidase (PE), assessed their ability to break down collagen and release PGP, and assayed for the presence of leukotriene A4 hydrolase (LTA4H) and its ability to degrade PGP. Acrolein treatment induced elevated production and functionality of collagen-degrading enzymes and generation of PGP fragments. Meanwhile, LTA4H levels and triaminopeptidase activity declined with increasing concentrations of acrolein thereby sparing PGP from enzymatic destruction. These findings suggest that acrolein exacerbates the acute inflammatory response mediated by neutrophils and sets the stage for chronic pulmonary and systemic inflammation.

Topics: Acrolein; Aminopeptidases; Chronic Disease; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Dose-Response Relationship, Drug; Humans; Inflammation; Leukotriene A4; Matrix Metalloproteinase 9; Neutrophils; Oligopeptides; Proline; Prolyl Oligopeptidases; Serine Endopeptidases

Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A4 (LXA4) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the "class switch" of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA4 to leukotriene B4 (LTB4) is depressed in CF BAL (p<0.01), even in the absence of infection (p<0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p<0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA4/LTB4 ratio (p=0.01, r=0.66) and with percentage macrophage composition of the BAL fluid (p<0.001, r=0.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA4/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung.

Topics: Anti-Bacterial Agents; Arachidonate 15-Lipoxygenase; Bronchoalveolar Lavage Fluid; Child; Child, Preschool; Cystic Fibrosis; Female; Humans; Inflammation; Leukotriene A4; Leukotriene B4; Lipoxins; Longitudinal Studies; Lung; Lung Diseases; Macrophages, Alveolar; Male; Neutrophils

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.

Topics: Animals; Disease Models, Animal; Humans; Inflammation; Leukotriene A4; Leukotriene B4; Lipoxins; Mitochondria; Mycobacterium Infections; Mycobacterium marinum; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Signal Transduction; Transcription, Genetic; Tuberculosis, Meningeal; Tumor Necrosis Factor-alpha; Zebrafish

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Arachidonate 5-Lipoxygenase; Cell Transformation, Neoplastic; Cyclooxygenase Inhibitors; Disease Models, Animal; Epoxide Hydrolases; Esophageal Neoplasms; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Leucine; Leukotriene A4; Neoplasms; Signal Transduction; Up-Regulation

Esophageal adenocarcinoma (EAC) is increasing at the most rapid rate of any cancer in the United States. An esophagogastroduodenal anastomosis (EGDA) surgical model in rats mimics human gastroesophageal reflux and results in EAC. Leukotriene A4 hydrolase (LTA4H), a protein overexpressed in EAC in this model, is a rate-limiting enzyme in the biosynthesis of leukotriene B4 (LTB4), a potent inflammatory mediator. We used this model and human EAC and non-tumor tissues to elucidate the expression pattern of LTA4H and to evaluate it as a target for chemoprevention.. LTA4H expression was examined by western blotting and immunohistochemistry. The functional role of LTA4H in carcinogenesis was investigated by use of an LTA4H inhibitor, bestatin, in the rat EGDA model. All statistical tests were two-sided.. LTA4H was overexpressed in all 10 rat EACs examined, compared with its level in normal rat tissue; it was also overexpressed in four of six human EAC tumor samples, compared with its level in adjacent non-tumor tissue. In tissue sections from 20 EGDA rats and 92 patients (86 with EAC, one with dysplasia, and five with columnar-lined esophagus), LTA4H was expressed in infiltrating inflammatory cells and overexpressed in the columnar cells of preinvasive lesions and cancers, especially in well-differentiated EACs, as compared with the basal cells of the normal esophageal squamous epithelium. Bestatin statistically significantly inhibited LTB4 biosynthesis in the esophageal tissues of EGDA rats (without bestatin = 8.28 ng/mg of protein; with bestatin = 4.68 ng/mg of protein; difference = 3.60, 95% CI = 1.59 to 5.61; P = .002) and reduced the incidence of EAC in the EGDA rats from 57.7% (15 of 26 rats) to 26.1% (6 of 23 rats) (difference = 31.6%, 95% CI = 0.3% to 56.2%; P = .042).. LTA4H overexpression appears to be an early event in esophageal adenocarcinogenesis and is a potential target for the chemoprevention of EAC.

Topics: Adenocarcinoma; Anastomosis, Surgical; Animals; Antibiotics, Antineoplastic; Blotting, Western; Chemoprevention; Disease Models, Animal; Duodenum; Epoxide Hydrolases; Esophageal Neoplasms; Esophagus; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Incidence; Inflammation; Leucine; Leukotriene A4; Rats; Stomach; Treatment Outcome; Up-Regulation

Leukotriene (LT) A(4) hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc enzyme that catalyzes the biosynthesis of LTB4, a potent lipid chemoattractant involved in inflammation, immune responses, host defense against infection, and PAF-induced shock. The high resolution crystal structure of LTA4H in complex with the competitive inhibitor bestatin reveals a protein folded into three domains that together create a deep cleft harboring the catalytic Zn(2+) site. A bent and narrow pocket, shaped to accommodate the substrate LTA(4), constitutes a highly confined binding region that can be targeted in the design of specific anti-inflammatory agents. Moreover, the structure of the catalytic domain is very similar to that of thermolysin and provides detailed insight into mechanisms of catalysis, in particular the chemical strategy for the unique epoxide hydrolase reaction that generates LTB(4).

Topics: Amino Acid Sequence; Aminopeptidases; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Epoxide Hydrolases; Humans; Hydrogen Bonding; Inflammation; Leucine; Leukotriene A4; Models, Molecular; Molecular Sequence Data; Multienzyme Complexes; Protein Structure, Secondary; Protein Structure, Tertiary; Thermolysin; Ytterbium; Zinc

LTB4 is a potent mediator of inflammation acting at local sites of inflammation. LTB4 increases the lymphocyte binding to and penetration through the endothelium. In this paper we demonstrate that while endothelial cells were unable to metabolize LTB4 from arachidonic acid they were able to hydrolyse LTA4 into LTB4 in a granulocyte-endothelial co-culture assay. This hydrolysis is markedly increased if endothelial cells were pretreated with IFN-gamma prior to the assay. The IFN-gamma induced effect was shown to be time- and dose-dependent. The ability of endothelial cells to hydrolyse LTA4 to LTB4 may provide an answer how LTB4 can be produced in large quantities by nonheamatopoetic cells (i.e. by endothelial cells) at sites of acute inflammation.

Topics: Animals; Cell Adhesion; Endothelium, Vascular; Granulocytes; Hydrolysis; In Vitro Techniques; Inflammation; Interferon-gamma; Leukotriene A4; Leukotriene B4; Leukotrienes; Lymphocytes; Rats; Rats, Inbred Strains

The arachidonic acid metabolism of guinea pig eosinophils isolated from either peritoneal cavity or bronchoalveolar lavages was studied by reverse-phase high-performance liquid chromatography. The purified eosinophils (95-100%) from either source released thromboxane B2 (TxB2), luekotriene B4 (LTB4) and 5-hydroxy eicosatetraenoic acid (5-HETE) following calcium ionophore A23187 stimulation. Quantification by radioimmunoassay indicated that maximal mediator output from the stimulated peritoneal cells was reached at 3 min after stimulation. The increase in production of TxB2 and LTB4 was correlated to increasing calcium ionophore A23187 concentration up to 1.0 micrograms/ml. In addition to calcium ionophore, the guinea pig peritoneal cells were also activated by f-met-leu-phe, phorbol 12-myristate, 13-acetate (PMA), and to lesser extent platelet-activating factor (PAF) to produce TxB2. LTB4 synthesis was stimulated by calcium ionophore, by f-met-leu-phe, as well as by unopsonized glucan, a particulate phagocytotic stimulus. The guinea pig eosinophils do not synthesize sulfidopeptide leukotrienes because of the absence of the specific LTA4 glutathione S-transferase. These results suggest that the guinea pig eosinophils differ from the human circulating eosinophils in the synthetic capacity of lipid mediators derived from arachidonic acid metabolism. This difference may be important in the understanding of the role of the eosinophils in inflammatory reactions such as that which occurs in the bronchial tissues of asthmatics.

Topics: Animals; Arachidonic Acids; Chromatography, High Pressure Liquid; Eosinophils; Female; Guinea Pigs; Inflammation; Leukotriene A4; Leukotriene B4; Leukotrienes; Radioimmunoassay; Thromboxane B2

Arachidonic acid undergoes two metabolic pathways in leukocytes. The first, catalysis by prostaglandin cyclo-oxygenase, yields the prostaglandin endoperoxides G2 and H2 and thromboxane A2, which induce rapid irreversible aggregation of human platelets and are potent inductors of smooth muscle contraction. The second pathway, catalysis by lipoxygenase, yields various hydroperoxy acids. In platelets, 12-hydroperoxyeicosatetraenoic acid is the predominant product; in polymorphonuclear leukocytes, 5-hydroperoxyeicosatetraenoic acid is formed. These are primarily reduced to 12-hydroxyeicosatetraenoic acid and 5-hydroxyeicosatetraenoic acid. 5-Hydroperoxyeicosatetraenoic acid may also be dehydrated to leukotriene A4. Enzymatic hydrolysis of leukotriene A4 yield leukotriene B4, a potent mediator of leukocyte function. Prostaglandins, thromboxanes, and some hydroxyeicosatetraenoic acids exert chemotactic effects on polymorphonuclear leukocytes. In this respect, leukotriene B4 is the most active compound derived from arachidonic acid. In vivo, adherence of leukocytes to the endothelium of microvessels near inflammatory areas and the sticking phenomenon of these cells are the initial hallmarks of an inflammatory response. In vitro, these responses seem to correspond with leukocyte aggregation and adherence. Leukotriene A4 may also react to form leukotriene C4 (a natural component of slow-reacting substance of anaphylaxis), leukotriene D4, leukotriene E4, and the 11-trans-isomers. All three leukotrienes are virtually unable to induce chemotaxis, enzyme release, or leukocyte aggregation, but they possess biologic properties previously attributed to slow-reacting substances, such as a potent effect on smooth muscle in the peripheral airway and an ability to markedly increase macromolecular permeability in venules. In addition to prolonging bleeding time and causing gastric ulcers, aspirin and other nonsteroidal anti-inflammatory drugs can trigger or aggravate an asthmatic attack. Aspirin can also trigger or aggravate urticaria, probably as a direct effect of thioether leukotrienes rather than from antibody mediation. Many nonsteroidal anti-inflammatory drugs increase formation of slow-reacting substance-A after challenge with allergen, perhaps by inhibiting cyclo-oxygenase, thereby releasing more arachidonic acid for metabolism by lipoxygenase. Alternatively, certain prostaglandins inhibit liberation of arachidonic acid from phospholipids; inhibiting their formation c

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Autacoids; Guinea Pigs; Humans; Inflammation; Leukotriene A4; Leukotriene B4; Prostaglandins; SRS-A; Thromboxanes

The leukotrienes are a family of potent mediators of hypersensitivity and inflammation. The application of sensitive and specific radioimmunoassays for leukotrienes has revealed the generation of significant quantities of several leukotrienes by leukocytes exposed to natural stimuli in the absence of exogenous arachidonic acid. The C6 peptide leukotrienes, LTC4 and LTD4, are potent vasoactive and smooth muscle contractile factors. LTB4 and other di-HETEs stimulate polymorphonuclear leukocyte function and suppress T-lymphocyte activities. The effects of LTB4 on T lymphocytes are subset-specific and include the activation of suppressor and cytotoxic T cells. Receptors for LTB4 on polymorphonuclear leukocytes are specific but exhibit considerable heterogeneity of binding affinity and may mediate different functional effects. The complexity of the pathways of generation and metabolism of leukotrienes, and of the leukotriene receptors, suggest that carefully defined systems will be needed to test the effects of pharmacological inhibitors and antagonists.

Topics: Arachidonic Acid; Arachidonic Acids; Drug Therapy; Humans; Hypersensitivity; Inflammation; Leukocytes; Leukotriene A4; Leukotriene B4; Lipoxygenase; Lymphocytes; Muscle, Smooth, Vascular; Neutrophils; Receptors, Immunologic; Receptors, Leukotriene B4; SRS-A

The glutathione-containing leukotriene C4 (LTC4) is a major mediator of smooth muscle contraction and is released by mast cells when antigen interacts with cell-bound IgE. Antigen-stimulated mast cells undergo phospholipase activation. We report a pathway of LTC4 production by mast cells that does not require phospholipase activation but depends on the interaction of activated neutrophils with unstimulated mast cells, using as an intermediate extracellular leukotriene A4 (LTA4). The epoxide LTA4 is released by neutrophils and, together with leukotriene B4 and 5-hydroxyeicosatetraenoic acid, constitutes the major lipoxygenase metabolites found in supernatants of stimulated neutrophils. Five minutes after activation of neutrophils by calcium ionophore A23187 we measured 136 pmol of extracellular LTA4 per 10(7) neutrophils (range 40-300, n = 7) by trapping the epoxide with alcohols. Therefore, we conclude that LTA4 is not just an intracellular leukotriene precursor but is released as a lipoxygenase metabolite. LTA4 is known to be stabilized by albumin and is efficiently converted by mast cells into LTC4 even at low LTA4 concentrations. The LTA4 complexed to albumin is converted into LTC4 rapidly and completely within 10-15 min. More than 50% of the LTA4 presented to mast cells is metabolized to LTC4 at concentrations of LTA4 between 0.2 and 2 nmol of LTA4 per 10(7) mast cells. This observation establishes a potential physiologic role for extracellular LTA4. Therefore, interactions between various cell types that release or utilize LTA4 may provide an important metabolic pathway for the production of leukotrienes.

Topics: Animals; Arachidonic Acids; Calcimycin; Humans; Inflammation; Leukotriene A4; Leukotriene B4; Lipoxygenase; Mast Cells; Mice; Neutrophils; Phospholipases; SRS-A

Topics: Arachidonic Acids; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; SRS-A

Topics: Arachidonic Acids; Asthma; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Leukotriene E4; SRS-A