The Role of Leukotrienes in Inflammation

  1. William R. Henderson, MD
  1. From the University of Washington School of Medicine, Seattle, Washington. Request for Reprints: William R. Henderson, Jr., MD, Department of Medicine, SJ-10, University of Washington School of Medicine, Seattle, WA 98195. Grant Support: In part by AI17758 and AI34578 from the National Institute of Allergy and Infectious Diseases, HL30542 from the National Heart, Lung, and Blood Institute, DK41978 from the National Institute of Diabetes and Digestive and Kidney Diseases, and grants from Abbott Laboratories and the Cystic Fibrosis Foundation.
     
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    Abstract

    Objective: To review the biochemistry and biological activities of leukotrienes, focusing on their role in the mediation of inflammatory diseases.

    Data Sources: MEDLINE (1966-1994), EMBASE (Excerpta Medica; 1974-1994), and other biomedical and drug directory databases (such as Pharmaprojects and IMSworld R&D Focus [1991-1994]) were searched to identify English-language articles (basic science, clinical trial research, and review articles) and abstracts of conference proceedings on leukotrienes and related terms.

    Study Selection: Basic science studies on leukotrienes and clinical research studies on the use of leukotriene inhibitors and antagonists in the treatment of inflammatory diseases such as asthma, psoriasis, rheumatoid arthritis, and ulcerative colitis.

    Data Extraction: Detailed summaries of data from basic science studies on the formation and actions of leukotrienes and from clinical studies of drugs that block the synthesis or receptor-mediated actions of leukotrienes.

    Data Synthesis: Leukotrienes are biologically active 5-lipoxygenase products of arachidonic acid metabolism that are involved in the mediation of various inflammatory disorders. Of these, leukotriene B4 (a potent chemoattractant for leukocytes) and the sulfidopeptide leukotrienes C4, D4, and E4 (which increase vascular permeability and constrict smooth muscle) exert their biological actions through specific ligand-receptor interactions. Selective leukotriene inhibitors and receptor antagonists are currently under evaluation in the treatment of various inflammatory diseases.

    Conclusions: Further data on the in vitro and in vivo activities of the leukotriene inhibitors and antagonists should clarify the role of leukotrienes in the pathogenesis of such inflammatory diseases as asthma, rheumatoid arthritis, and inflammatory bowel disease. Leukotriene inhibitors and antagonists will probably become important agents in the group of anti-inflammatory drugs.

    Leukotrienes, together with prostaglandins, thromboxanes, and lipoxins, are the major constituents of a group of biologically active oxygenated fatty acids known as eicosanoids [1]. Unlike many other biologically active molecules, the eicosanoids are not stored as preformed components of the immune response within their secreting cells but are synthesized de novo from membrane phospholipid through a cascade of enzymes known as the arachidonic acid cascade, named after the common precursor molecule of all eicosanoids (Figure 1).

    Figure 1.
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      Figure 1. 5-Lipoxygenase arachidonic acid products.

      The leukotrienes play a major role in the inflammatory response to injury; they have been implicated in the pathogenesis of several inflammatory diseases, most notably asthma, psoriasis, rheumatoid arthritis, and inflammatory bowel disease. The role of leukotrienes as inflammatory mediators of disease has made them therapeutic targets, and many inhibitors aimed at leukotriene biosynthetic or effector mechanisms are being developed.

      The primary purpose of this review of selected peer-reviewed articles on the biosynthesis, biochemistry, and biological actions of the leukotrienes is to help readers understand the therapeutic potential of these inhibitors.

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      Mobilization of Arachidonic Acid

      Arachidonic acid, present in the cell membrane in its esterified form, is the precursor molecule from which all eicosanoids are synthesized. Release of arachidonic acid is thought to be the rate-limiting step in a multistage biosynthetic process, which is mediated by specific enzymes that begin the process by inserting molecular oxygen into arachidonic acid. Figure 1 shows the structure of arachidonic acid and its 5-lipoxygenase metabolites, and Figure 2 shows in detail the process of leukotriene formation and the sites of action of these mediators.

      Figure 2.
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        Figure 2. Leukotriene formation in inflammatory cells and sites of action.

        The chain of eicosanoid biosynthesis begins after trauma, infection, and inflammation. The initial step in biosynthesis of eicosanoids is a receptor-mediated influx of Ca2+ ions that causes translocation of a phospholipase enzyme, cytosolic phospholipase A2, to the cell membrane [2, 3]. The enzyme then catalyzes the hydrolysis of the esterified form of arachidonic acid at its sn-2 position [4, 5]. Several phospholipase A2 enzymes of varying molecular weight that show relative specificity for the sn-2 ester linkage, including Ca2+ -sensitive and -insensitive forms, have been identified in cells such as macrophages, neutrophils, platelets, and mast cells, all of which are involved in eicosanoid biosynthesis [4, 5]. The activity of phospholipase A2 is increased by a phospholipase A2-activating protein that, when activated by cytokines such as tumor necrosis factor and interleukin-1, can lead to arachidonic acid release and leukotriene formation in leukocytes [6]. A secretory phospholipase A2 present on the surface of mast cells and other cells may also be involved in the liberation of arachidonic acid [7, 8]; this enzyme has been recovered in the synovial fluid of patients with rheumatoid arthritis [8-10].

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        Role of 5-Lipoxygenase in the Formation of Leukotriene A4

        Another enzyme is then called into play when 5-lipoxygenase, activated by Ca2+ and adenosine triphosphate, translocates from the cytosol to the cell membrane and begins to form leukotrienes. All leukotriene molecules are derived from a common precursor, leukotriene A4 (LTA4). This leukotriene, however, appears only after an intermediate step, in which 5-hydroperoxyeicosatetraenoic acid (HPETE) is formed through the action of 5-lipoxygenase acting in the presence of adenosine triphosphate, calcium ions [11-14], and the 5-lipoxygenase-activating protein [15-20]. Transfection of the 5-lipoxygenase-activating protein and 5-lipoxygenase complementary DNA (cDNA) into osteosarcoma cells has shown that both molecules are required for leukotriene synthesis [16]. Figure 2 shows the two-step molecular changes of arachidonic acid catalyzed by 5-lipoxygenase to form the unstable oxidation product LTA4[11, 21, 22].

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        Biosynthesis and Metabolism of Leukotriene B4 and the Cysteinyl Leukotrienes

        The formation of LTA4 is the last common step in the synthesis of LTB4 on the one hand and of the sulfidopeptide or cysteinyl leukotrienes (C4, D4, and E4) on the other. Leukotriene B4 is a dihydroxy acid formed from LTA4 through the action of LTA4 hydrolase, a cytosolic protein [23, 24]. Leukotriene B4 can undergo further oxidation at the 20 carbon atom to less active metabolites [1]. The string of cysteinyl leukotrienes is inaugurated when LTC4 synthase, a glutathione-S-transferase enzyme, converts LTA4 to the glutathione-containing sulfidopeptide LTC4[25-28]. Leukotrienes D4 and E4 are then formed when dipeptidases [29] remove first glutamic acid and then glycine sequentially from LTC4; both eicosanoids are biologically active. The cysteinyl leukotrienes finally undergo oxidative degradation by oxygen species released by activated phagocytes to form biologically inactive sulfoxides [30-32].

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        Sites of Leukotriene Biosynthesis

        The locations at which the leukotrienes are synthesized are determined by the cellular distribution of the enzymes controlling each stage of the biosynthetic pathway. Because 5-lipoxygenase is only found in cells of myeloid lineage, the synthesis of LTA4 is limited to these cells [17]. However, the enzymes determining the next step in the arachidonic acid cascade, either to LTB4 or to the sulfidopeptide leukotrienes, are more widely distributed; thus, metabolism of LTA4 may occur in an equally wide range of cell types. The export of LTA4 from cells that can actively synthesize it enables a much broader range of cells to act as leukotriene secretors.

        Primary Sites of Biosynthesis

        The distribution of 5-lipoxygenase is limited to a specific number of myeloid cells: neutrophils, eosinophils, monocytes, macrophages, mast cells, basophils, and B lymphocytes [17, 33]. Among the myeloid cells, considerable variation exists in both the type and quantity of leukotriene secreted. Most of these cells produce appreciable quantities of either LTB4 or LTC4 but not both, with the exception of human monocytes and macrophages. Monocytes and peritoneal macrophages release both LTB4 and LTD4 after they are exposed to nonimmunologic stimuli (for example, calcium ionophore A23187) or immunologic stimuli (for example, the interaction of IgG, IgA, and IgE with cell surface Fc receptors) [34-36]. All other cells identified as leukotriene secretors have been shown to release either LTB4 or C4 almost exclusively. Leukotriene C4 is the principal 5-lipoxygenase product released by activated eosinophils [37-39]. Eosinophil secretion of LTB4 can be identified after stimulation with the calcium ionophore A23187 but in quantities much less than those observed for LTC4[38, 39]. Similarly, dispersed purified pulmonary mast cells, stimulated with either the calcium ionophore A23187 or IgE, have been shown to produce primarily LTC4[40, 41]. In contrast, activated human neutrophils secrete LTB4 as their principal 5-lipoxygenase product [31]. Alveolar macrophages appear to produce a substantial excess of LTB4 to LTC4 after stimulation by calcium ionophore A23187, IgE, or IgG [42-45]. Immunoglobulin E-sensitized human basophils predominantly release LTB4 after they are stimulated by specific antigen, although these cells also release some LTC4[46].

        Secondary Sites of Biosynthesis

        Because LTA4 hydrolase and LTC4 synthase enzymes are widely distributed among different cell types, not all components of the arachidonic acid cycle must be in the same cellular location for leukotriene biosynthesis to proceed. Active secretion of LTA4 has been shown in vitro in both mast cells and neutrophils after stimulation with the calcium ionophore A23187, zymosan particles, and aggregated immunoglobulins [47-49]. The secretion of LTA4 could provide a means for marked amplification of leukotriene production at inflammatory sites. For example, both capillary endothelial cells and platelets contain LTC4 synthase and can generate LTC4 from neutrophil-derived LTA4[50-52]. Erythrocytes lack both phospholipase A2 and 5-lipoxygenase and thus lack the appropriate cellular machinery to produce LTA4. However, erythrocytes containing LTA4 hydrolase can use neutrophil-derived LTA4 to synthesize LTB4[53].

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        Leukotriene Receptors

        Leukotriene B4

        Two distinct binding sites of high and low affinity for LTB4 exist on the surface of neutrophils [54-56]. These G-coupled receptors are members of the rhodopsin-like receptor superfamily [54, 56]. Competitive binding studies in neutrophils and eosinophils have shown that the cis double bond at the C-6 position, the (5S,12R)-hydroxyl groups, and an intact eicosanoid backbone are structural and stereospecific requirements for LTB (4) binding to its receptor and induction of neutrophil chemotaxis [57-59].

        Leukotrienes C4, D4, and E4

        Controversy exists regarding the number and specificity of receptors for the sulfidopeptide leukotrienes and whether the pattern and specificity of the sulfidopeptide leukotriene receptors vary between animal and human models of inflammation. Although highly selective receptors for LTC4 have been identified in the lungs of rats [60] and guinea pigs [61], similar LTC4-specific receptors have not been identified in human lung tissue [62]. Instead, the demonstrated ability of LTC4 to contract bronchial smooth muscle may be explained by its bioconversion to LTD4.

        In human lung parenchyma, LTD4 interacts with high- and low-affinity receptors of the rhodopsin-like superfamily [63]. Selective LTD4 receptor antagonists inhibit both LTC4 and LTD4 contractile activity in human lung tissue, suggesting that LTC4 interacts with a common LTD4 binding site [62, 64, 65]. Because LTE4 competes for the LTD4 receptor, LTD4 and LTE4 probably interact with the same molecule on the cell surface.

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        Biological Consequences of Leukotriene B4 Secretion

        Leukotriene B4 secretion by myeloid cells as well as by nonmyeloid cells caused by transcellular metabolism induces a range of cellular and molecular responses that coordinate and amplify the inflammatory response. Although the chemotactic, chemokinetic, and vasoactive properties of LTB4 are perhaps the best elucidated, this molecule may also possess other biological activities, ranging from mediation of pain to modulation of diverse immune responses.

        Neutrophil Chemotaxis and Aggregation

        Leukotriene B4 is probably the most potent neutrophil chemotactic agent produced by the arachidonic acid cascade. Compared with other lipoxygenase byproducts that are chemotactic for neutrophils (for example, 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 5-, 12-, and 15-hydroperoxyeicosatetraenoic acid), LTB4 exerts substantially stronger chemokinetic effects on human cells [66, 67]. Intratracheal instillation of LTB4 induces the selective recruitment of functionally active neutrophils into bronchoalveolar lavage fluid in humans [68]. Subcutaneous injection of LTB4 into humans causes neutrophils to accumulate rapidly in the affected tissue [69, 70].

        Induction of Neutrophil-Endothelial Cell Adhesion

        Leukotriene B4 may play a pivotal role in the induction of neutrophil-endothelial cell adherence [71, 72]. In vivo, the topical application of LTB4 to the vascular network within the hamster cheek pouch results in immediate and reversible adherence of neutrophils to venular endothelial cells [73, 74]. Leukotriene B4-induced endothelial cell hyperadhesiveness for neutrophils depends on increased CD11/CD18 expression on the neutrophil surface and possibly a specific domain of the adhesion molecule CD54 found on endothelial cells [72, 75].

        Induction of Neutrophil Degranulation and Lysosomal Enzyme Release

        At nanomolar concentrations, LTB4 causes the release of substantial quantities of glucuronidase and lysozyme from neutrophils, although less effectively than the chemotactic fragment of the complement component C5 [76, 77]. Leukotriene B4-induced enzyme secretion is mediated by LTB4 recognition of a surface receptor of substantially lower affinity than that which mediates neutrophil aggregation, adherence to endothelium, and chemotaxis.

        Immune Modulation

        In vitro, LTB4 stimulates myelopoiesis, a phenomenon that may be linked to the secretion of significant quantities of LTB4 by human bone marrow cells [78, 79]. Leukotriene B4 augments interleukin-6 production in human monocytes by increasing both interleukin-6 gene transcription and messenger RNA (mRNA) stabilization [80, 81]; activation of nuclear factor (NF)-κ B and NF-interleukin-6 transcriptional factors may be important in this enhancement of interleukin-6 release [81]. Leukotriene B4 may modulate the production of other cytokines by stimulating gene transcription of the proto-oncogenes c-jun and c-fos in mononuclear cells [82].

        T-lymphocyte proliferation in response to mitogen also appears to depend on LTB4. Leukotriene B4 may exert its proliferative effect on T lymphocytes through the stimulation of interleukin-2 secretion [83]. Leukotriene B4 can replace interleukin-2 in the induction of interferon-γ by T cells [84]. Moreover, T cells treated with LTB4 appear to be able to suppress lymphocyte proliferation through interferon-γ-modulated augmentation of monocyte interleukin-1 secretion [85].

        Mediation of Pain in Inflammation

        Leukotriene B4 may be an important mediator of inflammatory pain. Injecting LTB4 into a rat paw results in a prolonged, neutrophil-dependent hyperalgesic reaction, which is associated with a sustained reduction in the nociceptive pressure threshold [86]. Under these circumstances, LTB4 appears to be roughly equipotent with bradykinin.

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        Biological Consequences of Secretion of Leukotrienes C4, D4, and E4

        Numerous studies have shown that the biological activity of the sulfidopeptide leukotrienes differs substantially from that of LTB4. The sulfidopeptide leukotrienes were first identified as the constituents of the slow-reacting substance of anaphylaxis [25]. As a result, their capacity for inducing airway, gastrointestinal, and mesangial smooth-muscle contraction is perhaps the best characterized of the biological activities exhibited by this family of molecules [1, 87]. However, like LTB4, the sulfidopeptide leukotrienes play a multifaceted role within the inflammatory process, inducing vasoconstriction, increasing vasopermeability, enhancing mucous secretion, and acting as immunomodulatory agents [1, 87].

        Induction of Smooth-Muscle Contraction

        The sulfidopeptide leukotrienes produce both vigorous prolonged contraction and resulting bronchoconstriction in both animal and human tissue, as shown by in vitro studies of animal and human bronchial specimens and in vivo studies in humans after inhalation of leukotrienes. In general, the cysteinyl leukotrienes have a potency as smooth-muscle spasmogens approximately 1000 times that of histamine. When applied to guinea pig tracheal and lung parenchymal preparations in vitro at picomolar doses, they cause sustained muscle contractions [88]. Moreover, the contractions that are induced by the sulfidopeptide leukotrienes are of a significantly more sustained nature than those that occur after treatment with histamine. In human bronchial or parenchymal strips, LTC4 and D4 exert a contractile potency 1000 times greater than either histamine or prostaglandin F2 α [89, 90].

        Modulation of Vascular Permeability and Vasoconstriction

        The sulfidopeptide leukotrienes are also intimately involved in changes within the vasculature. The increase in the permeability of the venular endothelium that allows proinflammatory cells to migrate to the site of inflammation is thought to be driven by the sulfidopeptide leukotrienes [91, 92]. Concomitant with the increase in vascular permeability and the extravasation of inflammatory cells, plasma components leak into the extravascular tissue, which leads to the development of edema. The addition of sulfidopeptide leukotrienes to the buccal mucosa of hamsters leads to submucosal edema [73], whereas subcutaneous injection in humans produces dermal edema [69].

        Furthermore, the smooth-muscle contractile effects exhibited by the sulfidopeptide leukotrienes, both in lung strips in vitro and on inhalation in vivo, also extend to the smooth muscle that constitutes a major part of the vascular wall. The resultant vasoconstriction has been shown experimentally in animal models. Leukotrienes C4 and D4 induce vasoconstriction in guinea pig skin [88] and the cheek pouches of hamsters [73]. Applying LTC4 to rat mucosal vessels causes such powerful vasoconstriction that segmental narrowing of the vessels produces stasis of blood between the constricted areas [93]. In humans, assessment of skin blanching at the site of LTC4 or LTD4 injection has shown that both molecules act as vasoconstrictive agents in human skin [69, 70]. Evidence also exists for prominent systemic effects initiated by these molecules. In vivo infusion of LTC4 or LTD4 into a major coronary vessel of the sheep and the systemic venous circulation of the rat produces coronary vasoconstriction; the systemic response to LTC4 in the rat includes renal vasoconstriction [94, 95].

        Enhancement of Mucous Secretion

        The sulfidopeptide leukotrienes enhance mucous secretion in the airways. Leukotrienes C4 and D4 are potent mucous secretagogues in human bronchial explants in vitro [96, 97] and in the trachea of dogs [98] and cats [99] in vivo.

        Immune Modulation

        The sulfidopeptide leukotrienes may also modulate the activity of several components of the immune system. Leukotrienes C4 and D4 stimulate the expansion of myeloid colonies treated with colony-stimulating factor [100]. These two leukotrienes may also be involved in the proliferative development of glomerular epithelial cells [101] and fibroblasts [102] in vitro. Leukotriene D4 enhances interleukin-1 production by human monocytes and can replace interleukin-2 in the induction of interferon-γ secretion by T lymphocytes [84].

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        Leukotriene Release in Inflammatory Diseases

        Leukotriene release has been implicated in the pathogenesis of asthma and other inflammatory disorders.

        Asthma and Allergic Rhinitis

        Atopic patients with asthma have a dual inflammatory response in the lungs after bronchial challenge with allergen. The early-phase asthmatic response resulting from IgE-mediated mast cell degranulation is followed several hours later by a late-phase bronchospastic response characterized by mucous glycoprotein release, interstitial edema, and eosinophil infiltration in the airways. Five minutes after endobronchial allergen challenge, LTC4 levels greater than those measured before challenge are detected in the bronchoalveolar lavage fluid of treated patients [103, 104]. An increase in urinary LTE4 levels is found 2 hours after allergen challenge [105]. Leukotriene E4 levels are also increased in the urine of patients having spontaneous asthmatic attacks [106].

        Increased levels of LTC4 are found in the nasal lavage fluid of aspirin-intolerant asthmatic patients after challenge with aspirin either orally [107] or topically [108]. In contrast, no release of sulfidopeptide leukotrienes is observed in nasal lavage fluid of aspirin-tolerant asthmatic patients or normal persons after they ingest aspirin [107]. At baseline, the urinary levels of LTE4 are approximately six times higher in asthmatic patients who are aspirin-intolerant than the levels of those who are aspirin-tolerant. Further, aspirin-intolerant asthmatic patients have a fourfold increase in urinary LTE4 levels 6 hours after aspirin challenge, whereas no increase is observed in the aspirin-tolerant asthmatic patients [109].

        Patients with allergic rhinitis experience both early- and late-phase periods of mucosal inflammation after nasal instillation of a specific allergen such as ragweed pollen; LTC4 is recovered in their nasal lavage fluids during both the early and late phases of inflammation after allergen challenge [110, 111].

        Cystic Fibrosis

        In normal persons, more than 90% of the cells recovered from the bronchoalveolar lavage fluid are alveolar macrophages. In contrast, the fluid of patients with cystic fibrosis and pulmonary disease contains a predominance of neutrophils and increased levels of neutrophil products such as elastase and myeloperoxidase [112]. Elevated levels of LTB4 and sulfidopeptide leukotrienes are found in the sputum [113-115], bronchoalveolar lavage fluid [116], and urine [117] of patients with this disease. When the LTB4 content of bronchoalveolar lavage epithelial lining fluid from 17 patients with cystic fibrosis was compared with that from 10 healthy persons, the LTB4 levels were 33.4-fold higher in the patients with cystic fibrosis [116]. Thus, LTB4 may be important in mediating the neutrophil infiltration of the airways observed in these patients.

        The Adult Respiratory Distress Syndrome

        As in patients with cystic fibrosis, neutrophils predominate in the bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. Further, persistently elevated levels of airway neutrophils are associated with increased mortality in patients with this disorder [118]. Elevated levels of LTB4 and sulfidopeptide leukotrienes have been recovered in the bronchoalveolar lavage fluid of patients with the syndrome as well as in that of those at risk for developing the disorder [119-121]. Persistence of abnormally high sulfidopeptide leukotriene levels has been shown over the initial 5-day period after diagnosis of the syndrome [122]. Thus, release of LTB4 may promote the influx of large numbers of neutrophils into the airways, and sulfidopeptide leukotrienes may be important mediators of the hypoxemia, permeability pulmonary edema, and reduced pulmonary compliance observed in patients with this disorder.

        Leukotriene B4 may also be an important mediator of pulmonary edema in ischemia and reperfusion lung injury [123, 124]. Elevated levels of LTB4 have been recovered in the bronchoalveolar lavage fluid of dogs with unilateral pulmonary artery occlusion or reperfusion injury [123].

        Glomerulonephritis

        Animal studies have shown an important role for LTB4 release in promoting leukocyte infiltration and degranulation in the glomeruli, which are characteristic features of glomerular immune injury. High basal synthesis of LTB4 by isolated glomeruli has been observed in rats with cationic bovine gammaglobulin-induced glomerulonephritis [125] and the early heterologous phase of nephrotoxic serum glomerulonephritis induced by high doses of anti-rat glomerular basement membrane immunoglobulin [126]. The renal plasma flow and glomerular filtrate rates decrease and the number of glomerular neutrophils increases after the in vivo intrarenal infusion of LTB4 in rats with nephrotoxic serum-induced glomerulonephritis [127]. In the accelerated phase of this glomerulonephritis model, urinary LTB4 levels correlate with the number of glomerular neutrophils, suggesting that urinary LTB4 levels could be a surrogate marker for acute glomerular inflammation [128]. Treating rats with anti-Thy 1 antibody causes a mesangial cell immune injury that mimics IgA and lupus mesangial nephropathies. In this animal model, glomerular release of LTB4 is associated with decreases in the glomerular filtration rate and renal flow rate [129]. Sulfidopeptide leukotrienes may reduce the glomerular filtration rate in glomerular immune injury by stimulating contraction of mesangial smooth-muscle cells [130]. Urinary LTE4 levels directly correlate with disease activity in patients with systemic lupus erythematosus and with a marked increase in LTE4 levels observed during periods of active disease [131].

        Rheumatoid Arthritis

        The blood and synovial fluids of patients with rheumatoid arthritis contain higher levels of LTB4 than those of normal persons [132, 133]. Synovial fluid levels of LTB4[134] and sulfidopeptide leukotrienes [135] are substantially higher in patients with rheumatoid arthritis than in patients with osteoarthritis; synovial fluid levels of leukocytes, immune complexes, and rheumatoid factor directly correlate with LTB4 levels in patients with rheumatoid arthritis [134]. In inflamed joints, infiltrating neutrophils are the probable source of LTB4 because the synovial lining cells from patients with rheumatoid arthritis generate little LTB4.

        Psoriasis

        An important inflammatory feature of psoriasis is neutrophil infiltration of the epidermal skin lesions. Higher levels of LTB4 are found in both acute and chronic psoriatic skin lesions than in normal skin [136-139]. Topical application of LTB4 on the skin of normal persons as well as on the noninvolved skin of psoriatic patients induces several pathologic features of psoriasis, such as edema and the formation of intraepidermal neutrophil microabscesses [136, 140]. Sulfidopeptide leukotriene levels are also increased in psoriatic skin lesions; a fourfold increase in urinary LTE4 levels has been found in patients with psoriasis compared with healthy controls [141].

        Inflammatory Bowel Disease

        Human colonic epithelial cells synthesize LTB4[142], which may promote the infiltration by neutrophils of injured colonic mucosa in patients with inflammatory bowel disease. The colonic mucosa of patients with ulcerative colitis and Crohn disease contains substantially elevated levels of LTB4 compared with similar tissue from normal persons [143-145], and LTB4 levels are substantially increased in the rectal dialysate fluid of these patients [146, 147].

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        Use of Leukotriene Inhibitors and Antagonists in Inflammatory Diseases

        As shown in Figure 3, several approaches have been adopted to inhibit or suppress leukotriene activity [148-150]. One of the most promising is aimed at inhibiting the 5-lipoxygenase enzyme, which plays a crucial role in the biosynthesis of LTA4Figure 3, Table 1. Inhibiting this enzyme would lead to suppression of the formation of both LTB4 and sulfidopeptide leukotrienes. The 5-lipoxygenase inhibitor most studied in clinical trials is zileuton. A hydroxyurea compound with chelating activity, zileuton inhibits the active-site iron of 5-lipoxygenase at concentrations that do not inhibit cyclooxygenase, 12-lipoxygenase, or 15-lipoxygenase [151]. Leukotriene formation can also be inhibited by compounds that bind tightly to 5-lipoxygenase-activating protein Figure 3, Table 1, thus preventing translocation of 5-lipoxygenase to the cell membrane. MK-0591 is a representative 5-lipoxygenase-activating protein inhibitor that effectively blocks leukotriene generation and is under clinical evaluation [152]. Whereas 5-lipoxygenase and 5-lipoxygenase-activating protein-inhibitor drugs proximally block the arachidonic acid cascade, thus preventing leukotriene formation, an alternative pharmacologic approach is distal selective blockade of the actions of LTB4 and sulfidopeptide leukotrienes by specific LTB4 and LTD4 receptor antagonists, respectively Figure 3, Table 2.

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        Table 1. Representative Leukotriene Inhibitors*
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        Table 2. Representative Leukotriene Antagonists
        Figure 3.
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          Figure 3. Leukotriene inhibitors and antagonists.

          The availability of selective leukotriene inhibitors and antagonists has helped elucidate the role of leukotrienes in the pathogenesis of many inflammatory diseases, most notably asthma, ulcerative colitis, rheumatoid arthritis, and psoriasis.

          Asthma and Allergic Rhinitis

          Initial studies using novel leukotriene receptor antagonists and inhibitors have confirmed a prominent role for leukotrienes as mediators of asthma. In patients with exercise-induced asthma, pretreatment with the selective LTD4 antagonist MK-571 attenuates the bronchospastic response to exercise challenge; this antagonist significantly reduced the maximal decrease in the forced expiratory volume in 1 second (FEV1) and recovery time after exercise [153]. In patients with moderately severe asthma, administration of MK-571 for 4 weeks has been shown to increase baseline FEV1 by 15%, lower daytime symptom scores, and decrease β (2-agonist) use by 30% [154]. The use of the selective LTD4 receptor antagonist MK-679 for 6 weeks was found to increase FEV1 by 18% and decrease the need for β2-agonists by 30% in asthmatic patients [155]. Another LTD4 antagonist, ICI 204,219, has been shown to inhibit both early- and late-phase asthma responses after inhalation of specific allergen [156]. In guinea pigs, the selective LTB4 receptor antagonist U-75302 inhibits both LTB4-induced chemotaxis of eosinophils in vitro and antigen-induced lung eosinophilia in vivo [157].

          The 5-lipoxygenase-activating protein inhibitor MK-886 partially inhibits early- and late-phase asthma responses after allergen challenge [158]. Specific inhibition of 5-lipoxygenase by zileuton significantly improves the bronchospastic response to inhalation of cold, dry air in patients with asthma [159]. A recent placebo-controlled multicenter study examined the effects of either 1.6 or 2.4 g of zileuton per day in 139 patients with moderately severe asthma [160]. A single 600-mg dose of zileuton immediately improved lung function, including a 14.6% increase in FEV1 over the baseline value [160]. After 4 weeks of treatment, zileuton improved airway function significantly and relieved symptoms, with the most marked changes occurring in the group receiving the 2.4 g/d. This group also had a 24% decrease in the use of β2-agonists compared with a 7% decrease in the placebo group [160]. The amelioration of bronchospasm was similar to that reported in previous studies of asthmatic patients treated with inhaled corticosteroids for a similar period.

          When the effect of the selective LTD4 antagonist SK&F 104353 on airway function in aspirin-intolerant persons with asthma was examined in a randomized, double-blind, crossover, placebo-controlled study [161], pretreatment with the drug was found to reduce the aspirin-induced decrease in FEV1 by a mean of 47% [161]. In a similar study of patients with aspirin-induced asthma, the 5-lipoxygenase inhibitor zileuton significantly reduced the decrease in FEV1 that occurred after aspirin ingestion [162]. In the zileuton trial, drug treatment also blocked the development of aspirin-induced angioedema, nasal congestion, and gastrointestinal symptoms.

          Zileuton also significantly reduces allergen-induced nasal congestion; it selectively blocks leukotriene release in patients with allergic rhinitis after challenge with specific allergen in nasal lavage fluids [163]. Pretreatment with another 5-lipoxygenase inhibitor, A-78773, significantly inhibits the increase in nasal lavage fluid protein and histamine levels observed after allergen challenge in patients with allergic rhinitis [164].

          Glomerulonephritis

          When mice were treated with the selective LTD4 receptor antagonist MCI-826, anti-glomerular basement membrane antibody-induced nephritis was blocked [165]. In rats with passive Heymann nephritis, a model of human membranous nephropathy, the 5-lipoxygenase-activating protein inhibitor MK-866 and the LTD4 receptor antagonist SK&F 104353 decrease proteinuria and ameliorate glomerular hemodynamic dysfunction, suggesting an important role for LTD4 in mediating these abnormalities in injured glomeruli [130].

          Rheumatoid Arthritis

          In a placebo-controlled study of the effect of the 5-lipoxygenase inhibitor zileuton in patients with active rheumatoid arthritis [166], clinical status substantially improved after 4 weeks in both the zileuton (1.6 g/d) and placebo groups. Compared with the patients receiving placebo, those treated with zileuton exhibited trends toward greater improvement in the number of painful and swollen joints and joint swelling index, but these differences were not statistically significant [166]. Oral methotrexate therapy significantly inhibits the ex vivo release of LTB4 by neutrophils from patients with active rheumatoid arthritis [167]. Auranofin also suppresses ex vivo neutrophil 5-lipoxygenase product synthesis [168].

          Psoriasis

          When applied topically to psoriatic plaques for 4 days, the selective 5-lipoxygenase inhibitor lonapalene has been shown to reduce LTB4 levels significantly in overlying skin chamber fluid compared with vehicle-treated sites; it also improved clinical scores in seven of nine patients after 2 and 4 weeks of treatment [169]. In 88 patients with localized lesions of psoriasis, 4 weeks of topical therapy with R 68 151, another 5-lipoxygenase inhibitor, was shown to significantly improve the mean symptom scores for scaling and erythema when compared with placebo [170]. In contrast to these results, which suggest clinical benefit with topical 5-lipoxygenase inhibitors, a 10-day course of oral treatment with the 5-lipoxygenase-activating protein inhibitor MK-886 had no effect on either clinical scores or LTB4 levels in skin lesions despite reducing urinary LTE4 levels by more than 70% in patients with psoriasis [171].

          Inflammatory Bowel Disease

          The selective LTB4 antagonist SC-41930 [172] and the 5-lipoxygenase-activating protein inhibitor MK-886 [173] significantly reduce acute colonic mucosal inflammation in animals with colitis. 5-Aminosalicylic acid, a 5-lipoxygenase inhibitor, inhibits LTB4 release in the rectal dialysates of patients with ulcerative colitis [146]. In an open, uncontrolled study of zileuton (800 mg/d) done in 11 patients with moderately severe ulcerative colitis [174], symptom scores were found to decrease significantly, and the appearance of the intestinal mucosa on sigmoidoscopy improved; however, no change in mucosal histologic findings was observed.

          Previous SectionNext Section

          Conclusions

          The discovery and steady exploration of the many oxygenation products that participate in the arachidonic acid cascade has been one of the outstanding advances in biomedical research in the last two decades. Although clinical effects of interventions that act primarily on the cyclooxygenase products of the cascade associated with inflammation and pain, such as aspirin and nonsteroidal anti-inflammatory drugs, have been widely studied, clinical studies of the 5-lipoxygenase cascade products, the leukotrienes, that mediate inflammation and have vasoactive effects are just being started. The accumulating evidence that the secretion of leukotrienes may initiate a chain of biochemical events that amplify inflammatory responses poses a challenge for those attempting to devise appropriate pharmacologic interventions because the complex of reactions may have both pathologic and homeostatic consequences. In this decade, basic science data and clinical evidence on the modes of action and clinical effects of the leukotrienes are beginning to come together. The more specific our knowledge of the biochemical changes becomes, the more likely it is that specific interventions producing more benefit than harm in reducing leukotriene-induced inflammation, vasodilation, and edema will be found.

          Previous Section
           

          References

          1. 1.↵
            Henderson WR Jr. Eicosanoids and platelet-activating factor in allergic respiratory diseases. Am Rev Respir Dis. 1991; 143:S86-90.
          2. 2.↵
            Sharp JD, White DL, Chiou XG, Goodson T, Gamboa GC, McClure D, et al. Molecular cloning and expression of human Ca(2+)-sensitive cytosolic phospholipase A2. J Biol Chem. 1991; 266:14850-3.
          3. 3.↵
            Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell. 1991; 65:1043-51.
          4. 4.↵
            Mayer RJ, Marshall LA. New insights on mammalian phospholipase A2(s); comparison of arachidonyl-selective and -nonselective enzymes. FASEB J. 1993; 7:339-48.
          5. 5.↵
            Glaser KB, Mobilio D, Chang JY, Senko N. Phospholipase A2 enzymes: regulation and inhibition. Trends Pharmacol Sci. 1993; 14:92-8.
          6. 6.↵
            Clark MA, gu LE, Conway TM, Dispoto J, Crooke ST, Bomalaski JS. Cloning of a phospholipase A2-activating protein. Proc Natl Acad Sci U S A. 1991; 88:5418-22.
          7. 7.↵
            Murakami M, Kudo I, Umeda M, Matsuzawa A, Takeda M, Komada M, et al. Detection of three distinct phospholipases A2 in cultured mast cells. J Biochem (Tokyo). 1992; 111:175-81.
          8. 8.↵
            Kramer RM, Hession C, Johansen B, Hayes G, McGray P, Chow EP, et al. Structure and properties of a human non-pancreatic phospholipase A (2). J Biol Chem. 1989; 264:5768-75.
          9. 9.↵
            Gonzalez-Buritica H, Khamashita MA, Hughes GR. Synovial fluid phospholipase A2s and inflammation. Ann Rheum Dis. 1989; 48:267-9.
          10. 10.↵
            Scott DL, White SP, Browning JL, Rosa JJ, Gelb MH, Sigler PB. Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. Science. 1991; 254:1007-10.
          11. 11.↵
            Rouzer CA, Samuelsson B. On the nature of the 5-lipoxygenase reaction in human leukocytes: enzyme purification and requirement for multiple stimulatory factors. Proc Natl Acad Sci U S A. 1985; 82:6040-4.
          12. 12.↵
            Goetze AM, Fayer L, Bouska J, Bornemeier D, Carter GW. Purification of a mammalian 5-lipoxygenase from rat basophilic leukemia cells. Prostaglandins. 1985; 29:689-701.
          13. 13.↵
            Matsumoto T, Funk CD, Rangstromdmark O, Hoo JO, Jornvall H, Samuelsson B. Molecular cloning and amino acid sequence of human 5-lipoxygenase. Proc Natl Acad Sci U S A. 1988; 85:26-30.
          14. 14.↵
            Balcarek JM, Theisen TW, Cook MN, Varrichio A, Hwang SM, Strohsaker MW, et al. Isolation and characterization of a cDNA clone encoding rat 5-lipoxygenase. J Biol Chem. 1988; 263:13937-41.
          15. 15.↵
            Miller DK, Gillard JW, Vickers PJ, Sadowski S, Leveille C, Mancini JA, et al. Identification and isolation of a membrane protein necessary for leukotriene production. Nature. 1990; 343:278-81.
          16. 16.↵
            Dixon RA, Diehl RE, Opas E, Rands E, Vickers PJ, Evans JF, et al. Requirement of a 5-lipoxygenase-activating protein for leukotriene synthesis. Nature. 1990; 343:282-4.
          17. 17.↵
            Reid GK, Kargman S, Vickers PJ, Mancini JA, Leveille C, Ethier D, et al. Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. J Biol Chem. 1990; 265:19818-23.
          18. 18.↵
            Rouzer CA, Kargman S. Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187. J Biol Chem. 1988; 263:10980-8.
          19. 19.↵
            Rouzer CA, Ford-Hutchinson AW, Morton HE, Gillard JW. MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J Biol Chem. 1990; 265:1436-42.
          20. 20.↵
            Wong A, Cook MN, Foley JJ, Sarau HM, Marshall P, Hwang SM. Influx of extracellular calcium is required for the membrane translocation of 5-lipoxygenase and leukotriene synthesis. Biochemistry. 1991; 30:9346-54.
          21. 21.↵
            Shimizu T, Izumi T, Seyama Y, Tadokoro K, Rangstromdmark O, Samuelsson B. Characterization of leukotriene A4 synthase from murine mast cells: evidence for its identity to arachidonate 5-lipoxygenase. Proc Natl Acad Sci U S A. 1986; 83:4175-9.
          22. 22.↵
            Hogaboom GK, Cook M, Newton JF, Varrichio A, Shorr RG, Sarau HM, et al. Purification, characterization, and structural properties of a single protein from rat basophilic leukemia (RBL-1) cells possessing 5-lipoxygenase and leukotriene A4 synthetase activities. Mol Pharmacol. 1986; 30:510-9.
          23. 23.↵
            Borgeat P, Samuelsson B. Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxyeicosatetraenoic acid. J Biol Chem. 1979; 254:2643-6.
          24. 24.↵
            Rangstromdmark O, Shimizu T, Jornvall H, Samuelsson B. Leukotriene A4 hydrolase in human leukocytes. Purification and properties. J Biol Chem. 1984; 259:12339-45.
          25. 25.↵
            Murphy RC, Hammarstrom S, Samuelsson B. Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci U S A. 1979; 76:4275-9.
          26. 26.↵
            Penrose JF, Gagnon L, Goppelt-Struebe M, Myers P, Lam BK, Jack RM, et al. Purification of human leukotriene C4 synthase. Proc Natl Acad Sci U S A. 1992; 89:11603-6.
          27. 27.↵
            Nicholson DW, Klemba MW, Rasper DM, Metters KM, Zamboni RJ, Ford-Hutchinson AW. Purification of human leukotriene C4 synthase from dimethylsulfoxide-differentiated U937 cells. Eur J Biochem. 1992; 209:725-34.
          28. 28.↵
            Ali A, Zamboni RJ, Ford-Hutchinson AW, Nicholson DW. Photoaffinity labelling of human leukotriene C4 synthase in THP-1 cell membranes. FEBS Lett. 1993; 317:195-201.
          29. 29.↵
            Anderson ME, Allison RD, Meister A. Interconversion of leukotrienes catalyzed by purified γ-glutamyl transpeptidase; concomitant formation of leukotriene D4 and γ-glutamyl amino acids. Proc Natl Acad Sci U S A. 1982; 79:1088-91.
          30. 30.↵
            Henderson WR, Jorg A, Klebanoff SJ. Eosinophil peroxidase-mediated inactivation of leukotrienes B4, C4 and D4. J Immunol. 1982; 128:2609-13.
          31. 31.↵
            Henderson WR, Klebanoff SJ. Leukotriene production and inactivation by normal, chronic granulomatous disease and myeloperoxidase-deficient neutrophils. J Biol Chem. 1983; 258:13522-7.
          32. 32.↵
            Henderson WR. Formation and oxidative degradation of leukotrienes by eosinophils and neutrophils. In: Samuelsson B, Berti F, Folco GC, Velo GP, eds. Drugs Affecting Leukotrienes and Other Eicosanoid Pathways. New York: Plenum Press; 1985:339-49.
          33. 33.↵
            Jakobsson P-J, Odlander B, Steinhilber D, Rose A, Claesson HE. Human B lymphocytes possess 5-lipoxygenase activity and convert arachidonic acid to leukotriene B4. Biochem Biophys Res Commun. 1991; 178:302-8.
          34. 34.↵
            Goldyne ME, Burrish GF, Poubelle P, Borgeat P. Arachidonic acid metabolism among human mononuclear leukocytes. Lipoxygenase-related pathways. J Biol Chem. 1984; 259:8815-9.
          35. 35.↵
            Ferreri NR, Howland WC, Spiegelberg HL. Release of leukotrienes C4 and B4 and prostaglandin E2 from human monocytes stimulated with aggregated IgG, IgA, and IgE. J Immunol. 1986; 136:4188-93.
          36. 36.↵
            Williams JD, Czop JK, Austen KF. Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators. J Immunol. 1984; 132:3034-40.
          37. 37.↵
            Jorg A, Henderson WR, Murphy RC, Klebanoff SJ. Leukotriene generation by eosinophils. J Exp Med. 1982; 155:390-402.
          38. 38.↵
            Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4. Proc Natl Acad Sci U S A. 1983; 80:7626-30.
          39. 39.↵
            Henderson WR, Harley JB, Fauci AS. Arachidonic acid metabolism in normal and hypereosinophilic syndrome human eosinophils: generation of leukotrienes B4, C4, D4 and 15-lipoxygenase products. Immunology. 1984; 51:679-86.
          40. 40.↵
            MacGlashan DW Jr, Schleimer RP, Peters SP, Schulman ES, Adam GK 3d, Newball HH, et al. Generation of leukotrienes by purified human lung mast cells. J Clin Invest. 1982; 70:747-51.
          41. 41.↵
            Levi-Schaffer F, Austen KF, Caulfield JP, Hein A, Gravallese PM, Stevens RL. Co-culture of human lung-derived mast cells with mouse 3T3 fibroblasts: morphology and IgE-mediated release of histamine, prostaglandin D2, and leukotrienes. J Immunol. 1987; 139:494-500.
          42. 42.↵
            Fels AO, Pawlowski NA, Cramer EB, King TK, Cohn ZA, Scott WA. Human alveolar macrophages produce leukotriene B4. Proc Natl Acad Sci U S A. 1982; 79:7866-70.
          43. 43.↵
            Martin TR, Altman LC, Albert RK, Henderson WR. Leukotriene B4 production by the human alveolar macrophage: a potential mechanism for amplifying inflammation in the lung. Am Rev Respir Dis. 1984; 129:106-11.
          44. 44.↵
            Martin TR, Raugi G, Merritt TL, Henderson WR Jr. Relative contribution of leukotriene B4 to the neutrophil chemotactic activity produced by the resident human alveolar macrophage. J Clin Invest. 1987; 80:1114-24.
          45. 45.↵
            Rankin JA, Schrader CE, Smith SM, Lewis RA. Recombinant interferon-γ primes alveolar macrophages cultured in vitro for the release of leukotriene B4 in response to IgG stimulation. J Clin Invest. 1989; 83:1691-700.
          46. 46.↵
            Sorensen LS, Mullarkey MF, Bean MA, Mochizuki DY, Chi EY, Henderson WR. Propagation and characterization of human blood basophils. Int Arch Allergy Appl Immunol. 1988; 86:267-80.
          47. 47.↵
            Dahinden CA, Clancy RM, Gross M, Chiller JM, Hugli TE. Leukotriene C4 production by murine mast cells: evidence of a role for extracellular leukotriene A4. Proc Natl Acad Sci U S A. 1985; 82:6632-6.
          48. 48.↵
            McGee JE, Fitzpatrick FA. Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis. Proc Natl Acad Sci U S A. 1986; 83:1349-53.
          49. 49.↵
            Sun FF, McGuire JC. Metabolism of arachidonic acid by human neutrophils. Characterization of the enzymatic reactions that lead to the synthesis of leukotriene B4. Biochim Biophys Acta. 1984; 794:56-64.
          50. 50.↵
            Feinmark SJ, Cannon PJ. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. J Biol Chem. 1986; 261:16466-72.
          51. 51.↵
            Claesson HE, Haeggstrom J. Human endothelial cells stimulate leukotriene synthesis and convert granulocyte released leukotriene A4 into leukotrienes B4, C4, D4 and E4. Eur J Biochem. 1988; 173:93-100.
          52. 52.↵
            Maclouf JA, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4. J Biol Chem. 1988; 263:174-81.
          53. 53.↵
            Fitzpatrick F, Liggett W, McGee J, Bunting S, Morton D, Samuelsson B. Metabolism of leukotriene A4 by human erythrocytes. A novel cellular source of leukotriene B4. J Biol Chem. 1984; 259:11403-7.
          54. 54.↵
            Goldman DW, Goetzl EJ. Specific binding of leukotriene B4 to receptors on human polymorphonuclear leukocytes. J Immunol. 1982; 129:1600-4.
          55. 55.↵
            Lin AH, Ruppel PL, Gorman RR. Leukotriene B4 binding to human neutrophils. Prostaglandins. 1984; 28:837-49.
          56. 56.↵
            Goldman DW, Goetzl EJ. Heterogeneity of human polymorphonuclear leukocyte receptors for leukotriene B4. Identification of a subset of high affinity receptors that transduce the chemotactic response. J Exp Med. 1984; 159:1027-41.
          57. 57.↵
            Ng CF, Sun FF, Taylor BM, Wolin MS, Wong PY. Functional properties of guinea pig eosinophil leukotriene B4 receptor. J Immunol. 1991; 147:3096-103.
          58. 58.↵
            Bomalaski JS, Mong S. Binding of leukotriene B4 and its analogs to human polymorphonuclear leukocyte membrane receptors. Prostaglandins. 1987; 33:855-67.
          59. 59.↵
            Leblanc Y, Fitzsimmons BJ, Charleson S, Alexander P, Evans JF, Rokach J. Analogs of leukotriene B4: effects of modification of the hydroxyl groups on leukocyte aggregation and binding to leukocyte leukotriene B4 receptors. Prostaglandins. 1987; 33:617-25.
          60. 60.↵
            Pong SS, DeHaven RN, Kuehl FA Jr, Egan RW. Leukotriene C4 binding to rat lung membranes. J Biol Chem. 1983; 258:9616-9.
          61. 61.↵
            Hogaboom GK, Mong S, Wu HL, Crooke ST. Peptidoleukotrienes: distinct receptors for leukotriene C4 and D4 in the guinea-pig lung. Biochem Biophys Res Commun. 1983; 116:1136-43.
          62. 62.↵
            Buckner CK, Krell RD, Laravuso RB, Coursin DB, Bernstein PR, Will JA. Pharmacological evidence that human intralobar airways do not contain different receptors that mediate contractions to leukotriene C4 and leukotriene D4. J Pharmacol Exp Ther. 1986; 237:558-62.
          63. 63.↵
            Rovati GE, Giovanazzi S, Mezzetti M, Nicosia S. Heterogeneity of binding sites for ICI 198,615 in human lung parenchyma. Biochem Pharmacol. 1992; 44:1411-5.
          64. 64.↵
            Buckner CK, Saban R, Castleman WL, Will JA. Analysis of leukotriene receptor antagonists on isolated human intralobar airways. Ann N Y Acad Sci. 1988; 524:181-6.
          65. 65.↵
            Aharony D, Falcone RC. Binding of tritiated LTD-4 and the peptide leukotriene antagonist tritiated ICI-198615 to receptors on human lung membranes. In: Zor U, Naor Z, Danon A, eds. New Trends in Lipid Mediators Research. Basel: Karger; 1989:67-71.
          66. 66.↵
            Goetzl EJ, Sun FF. Generation of unique mono-hydroxy-eicosatetraenoic acids from arachidonic acid by human neutrophils. J Exp Med. 1979; 150:406-11.
          67. 67.↵
            Palmer RM, Stepney RJ, Higgs GA, Eakins KE. Chemokinetic activities of arachidonic and lipoxygenase products on leukocytes of different species. Prostaglandins. 1980; 20:411-8.
          68. 68.↵
            Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest. 1989; 84:1609-19.
          69. 69.↵
            Soter NA, Lewis RA, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4, and LTB4) in human skin. J Invest Dermatol. 1983; 80:115-9.
          70. 70.↵
            Camp RD, Coutts AA, Greaves MW, Kay AB, Walport MJ. Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4. Br J Pharmacol. 1983; 80:497-502.
          71. 71.↵
            Hoover RL, Karnovsky MJ, Austen KF, Corey EJ, Lewis RA. Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion. Proc Natl Acad Sci U S A. 1984; 81:2191-3.
          72. 72.↵
            Tonnesen MG. Neutrophil-endothelial cell interactions: mechanisms of neutrophil adherence to vascular endothelium. J Invest Dermatol. 1989; 93:53S-8S.
          73. 73.↵
            Dahlen SE, Bjork J, Hedqvist P, Arfors KE, Hammarstrom S, Lindgren JA, et al. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A. 1981; 78:3887-91.
          74. 74.↵
            Bjork J, Hedqvist P, Arfors KE. Increase in vascular permeability induced by leukotriene B4 and the role of polymorphonuclear leukocytes. Inflammation. 1982; 6:189-200.
          75. 75.↵
            Palmblad JE, Lerner R. Leukotriene B4-induced hyperadhesiveness of endothelial cells for neutrophils: relation to CD54. Clin Exp Immunol. 1992; 90:300-4.
          76. 76.↵
            Bass DA, Thomas MJ, Goetzl EJ, DeChatelet LR, McCall CE. Lipoxygenase-derived products of arachidonic acid mediate stimulation of hexose uptake in human polymorphonuclear leukocytes. Biochem Biophys Res Commun. 1981; 100:1-7.
          77. 77.↵
            Sha'afi RI, Naccache PH, Molski TF, Borgeat P, Goetzl EJ. Cellular regulatory role of leukotriene B4: its effects on cation homeostasis in rabbit neutrophils. J Cell Physiol. 1981; 108:401-8.
          78. 78.↵
            Claesson HE, Dahlberg N, Gahrton G. Stimulation of human myelopoiesis by leukotriene B4. Biochem Biophys Res Commun. 1985; 131:579-85.
          79. 79.↵
            Stenke L, Lauren L, Reizenstein P, Lindgren JA. Leukotriene production by fresh human bone marrow cells: evidence of altered lipoxygenase activity in chronic myelocytic leukemia. Exp Hematol. 1987; 15:203-7.
          80. 80.↵
            Rola-Pleszczynski M, Stankova J. Leukotriene B4 enhances interleukin-6 (IL-6) production and IL-6 messenger RNA accumulation in human monocytes in vitro: transcriptional and posttranscriptional mechanisms. Blood. 1992; 80:1004-11.
          81. 81.↵
            Brach MA, de Vos S, Arnold C, Gruss HJ, Mertelsmann R, Herrmann F. Leukotriene B4 transcriptionally activates interleukin-6 expression involving NK-κ B and NF-IL6. Eur J Immunol. 1992; 22:2705-11.
          82. 82.↵
            Stankova J, Rola-Pleszczynski M. Leukotriene B4 stimulates c-fos and c-jun gene transcription and AP-1 binding activity in human monocytes. Biochem J. 1992; 282:625-9.
          83. 83.↵
            Rola-Pleszczynski M, Chavaillaz PA, Lemaire I. Stimulation of interleukin 2 and interferon γ production by leukotriene B4 in human lymphocyte cultures. Prostaglandins Leukot Med. 1986; 23:207-10.
          84. 84.↵
            Johnson HM, Russell JK, Torres BA. Second messenger role of arachidonic acid and its metabolites in interferon-γ production. J Immunol. 1986; 137:3053-6.
          85. 85.↵
            Rola-Pleszczynski M, Bouvrette L, Gingras D, Girard M. Identification of interferon-γ as the lymphokine that mediates leukotriene B4-induced immunoregulation. J Immunol. 1987; 139:513-7.
          86. 86.↵
            Levine JD, Lau W, Kwiat G, Goetzl EJ. Leukotriene B4 produces hyperalgesia that is dependent on polymorphonuclear leukocytes. Science. 1984; 225:743-5.
          87. 87.↵
            Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987; 237:1171-6.
          88. 88.↵
            Drazen JM, Austen KF, Lewis RA, Clark DA, Goto G, Marfat A, et al. Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc Natl Acad Sci U S A. 1980; 77:4354-8.
          89. 89.↵
            Dahlen SE, Hansson G, Hedqvist P, Bjorck T, Granstrom E, Dahlen B. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with release of leukotrienes C4, D4, and E4. Proc Natl Acad Sci U S A. 1983; 80:1712-6.
          90. 90.↵
            Hedqvist P, Dahlen SE, Gustafsson L, Hammarstrom S, Samuelsson B. Biological profile of leukotrienes C4 and D4. Acta Physiol Scand. 1980; 110:331-3.
          91. 91.↵
            Peck MJ, Piper PJ, Williams TJ. The effect of leukotrienes C4 and D4 on the microvasculature of guinea-pig skin. Prostaglandins. 1981; 21:315-21.
          92. 92.↵
            Joris I, Majno G, Corey EJ, Lewis RA. The mechanism of vascular leakage induced by leukotriene E4. Am J Pathol. 1987; 126:19-24.
          93. 93.↵
            Whittle BJ, Oren-Wolman N, Guth PH. Gastric vasoconstrictor actions of leukotriene C4, PGF2 α, and thromboxane mimetic U-46619 on rat submucosal microcirculation in vivo. Am J Physiol. 1985; 248:G580-6.
          94. 94.↵
            Michelassi F, Landa L, Hill RD, Lowenstein E, Watkins WD, Petkau AJ, et al. Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. Science. 1982; 217:841-3.
          95. 95.↵
            Badr KF, Baylis C, Pfeffer JM, Pfeffer MA, Soberman RJ, Lewis RA, et al. Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat. Circ Res. 1984; 54:492-9.
          96. 96.↵
            Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner M. Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis. 1982; 126:449-51.
          97. 97.↵
            Coles SJ, Neill KH, Reid LM, Austen KF, Nii Y, Corey EJ, et al. Effects of leukotrienes C4 and D4 on glycoprotein and lysozyme secretion by human bronchial mucosa. Prostaglandins. 1983; 25:155-70.
          98. 98.↵
            Johnson HG, McNee ML. Secretogogue responses of leukotriene C4, D4: comparison of potency in canine trachea in vivo. Prostaglandins. 1983; 25:237-43.
          99. 99.↵
            Peatfield AC, Piper PJ, Richardson PS. The effect of leukotriene C4 on mucin release into the cat trachea in vivo and in vitro. Br J Pharmacol. 1982; 77:391-3.
          100. 100.↵
            Miller AM, Weiner RS, Ziboh VA. Evidence for the role of leukotrienes C4 and D4 as essential intermediates in CSF-stimulated human myeloid colony formation. Exp Hematol. 1986; 14:760-5.
          101. 101.↵
            Baud L, Sraer J, Perez J, Nivez MP, Ardaillou R. Leukotriene C4 binds to human glomerular epithelial cells and promotes their proliferation in vitro. J Clin Invest. 1985; 76:374-7.
          102. 102.↵
            Baud L, Perez J, Denis M, Ardaillou R. Modulation of fibroblast proliferation by sulfidopeptide leukotrienes: effect of indomethacin. J Immunol. 1987; 138:1190-5.
          103. 103.↵
            Wenzel SE, Westcott JY, Larsen GL. Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses. J Allergy Clin Immunol. 1991; 87:540-8.
          104. 104.↵
            Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY. Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis. 1990; 142:112-9.
          105. 105.↵
            Sladek K, Dworski R, Fitzgerald GA, Buitkus KL, Block FJ, Marney SR Jr, et al. Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. Am Rev Respir Dis. 1990; 141:1441-5.
          106. 106.↵
            Drazen JM, O'Brien J, Sparrow D, Weiss ST, Martins MA, Israel E, et al. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis. 1992; 146:104-8.
          107. 107.↵
            Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis. 1988; 137:847-54.
          108. 108.↵
            Picado C, Ramis I, Rosello J, Prat J, Bulbena O, Plaza V, et al. Release of peptide leukotriene into nasal secretions after local instillation of aspirin in aspirin-sensitive asthmatic patients. Am Rev Respir Dis. 1992; 145:65-9.
          109. 109.↵
            Christie PE, Tagari P, Ford-Hutchinson AW, Charlesson S, Chee P, Arm JP, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis. 1991; 143:1025-9.
          110. 110.↵
            Creticos PS, Peters SP, Adkinson NF Jr, Naclerio RM, Hayes EC, Norman PS, et al. Peptide leukotriene release after antigen challenge in patients sensitive to ragweed. N Engl J Med. 1984; 310:1626-30.
          111. 111.↵
            Naclerio RM, Proud D, Togias AG, Adkinson NF Jr, Meyers DA, Kagey-Sobotka A, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med. 1985; 313:65-70.
          112. 112.↵
            Konstan MW, Norvell TM, Hilliard KA, Shiratsuchi H, Berger M. Serial bronchoalveolar lavage to evaluate inflammation in cystic fibrosis lung disease. Pediatr Pulmonol (Abstract). 1990; 9(Suppl 5):273.
          113. 113.↵
            Cromwell O, Walport MJ, Morris HR, Taylor GW, Hodson ME, Batten J, et al. Identification of leukotrienes D and B in sputum from cystic fibrosis patients. Lancet. 1981; 2:164-5.
          114. 114.↵
            Zakrzewski JT, Barnes NC, Piper PJ, Costello JF. Detection of sputum eicosanoids in cystic fibrosis and in normal saliva by bioassay and radioimmunoassay. Br J Clin Pharmacol. 1987; 23:19-27.
          115. 115.↵
            Spencer DA, Sampson AP, Green CP, Costello JF, Piper PJ, Price JF. Sputum cysteinyl-leukotriene levels correlate with the severity of pulmonary disease in children with cystic fibrosis. Pediatr Pulmonol. 1992; 12:90-4.
          116. 116.↵
            Konstan MW, Walenga RW, Hilliard KA, Hilliard JB. Leukotriene B4 is markedly elevated in epithelial lining fluid of patients with cystic fibrosis. Am Rev Respir Dis. 1993; 48:896-901.
          117. 117.↵
            Sampson AP, Spencer DA, Green CP, Piper PJ, Price JF. Leukotrienes in the sputum and urine of cystic fibrosis children. Br J Clin Pharmacol. 1990; 30:861-9.
          118. 118.↵
            Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994; 150:113-22.
          119. 119.↵
            Matthay MA, Eschenbacher WL, Goetzl EJ. Elevated concentrations of leukotriene D4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. J Clin Immunol. 1984; 4:479-83.
          120. 120.↵
            Antonelli M, Bufi M, De Blasi RA, Crimi G, Conti G, Mattia C, et al. Detection of leukotrienes B4, C4 and of their isomers in arterial, mixed venous blood and bronchoalveolar lavage fluid from ARDS patients. Intensive Care Med. 1989; 15:296-301.
          121. 121.↵
            Stephenson AH, Lonigro AJ, Hyers TM, Webster RO, Fowler AA. Increased concentrations of leukotrienes in bronchoalveolar lavage fluid of patients with ARDS or at risk for ARDS. Am Rev Respir Dis. 1988; 138:714-9.
          122. 122.↵
            Bernard GR, Korley V, Chee P, Swindell B, Ford-Hutchinson AW, Tagari P. Persistent generation of peptido leukotrienes in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1991; 144:263-7.
          123. 123.↵
            Su M, Chi EY, Bishop MJ, Henderson WR Jr. Lung mast cells increase in number and degranulate during pulmonary artery occlusion/reperfusion injury in dogs. Am Rev Respir Dis. 1993; 147:448-56.
          124. 124.↵
            Goldman G, Welbourn R, Klausner JM, Kobzik L, Valeri CR, Shepro D, et al. Mast cells and leukotrienes mediate neutrophil sequestration and lung edema after remote ischemia in rodents. Surgery. 1992; 112:578-86.
          125. 125.↵
            Rahman MA, Nakazawa M, Emancipator SN, Dunn MJ. Increased leukotriene B4 synthesis in immune injured rat glomeruli. J Clin Invest. 1988; 81:1945-52.
          126. 126.↵
            Lianos EA. Synthesis of hydroxyeicosatetraenoic acids and leukotrienes in rat nephrotoxic serum glomerulonephritis. Role of anti-glomerular basement membrane antibody dose, complement, and neutrophiles. J Clin Invest. 1988; 82:427-35.
          127. 127.↵
            Yared A, Albrightson-Winslow C, Griswold D, Takahashi K, Fogo A, Badr KF. Functional significance of leukotriene B4 in normal and glomerulonephritic kidneys. J Am Soc Nephrol. 1991; 2:45-56.
          128. 128.↵
            Lefkowith JB, Pippin J, Nagamatsu T, Lee V. Urinary eicosanoids and the assessment of glomerular inflammation. J Am Soc Nephrol. 1992; 2:1560-7.
          129. 129.↵
            Bresnahan BA, Wu S, Fenoy FJ, Roman RJ, Lianos EA. Mesangial cell immune injury. Hemodynamic role of leukocyte- and platelet-derived eicosanoids. J Clin Invest. 1992; 90:2304-12.
          130. 130.↵
            Katoh T, Lianos EA, Fukunaga M, Takahashi K, Badr KF. Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis. J Clin Invest. 1993; 91:1507-15.
          131. 131.↵
            Hackshaw KV, Voelkel NF, Thomas RB, Westcott JY. Urine leukotriene E4 levels are elevated in patients with active systemic lupus erythematosus. J Rheumatol. 1992; 19:252-8.
          132. 132.↵
            Davidson EM, Rae SA, Smith MJ. Leukotriene B4, a mediator of inflammation present in synovial fluid in rheumatoid arthritis. Ann Rheum Dis. 1983; 42:677-9.
          133. 133.↵
            Belch JJ, O'Dowd A, Ansell D, Sturrock RD. Leukotriene B4 production by peripheral blood neutrophils in rheumatoid arthritis. Scand J Rheumatol. 1989; 18:213-9.
          134. 134.↵
            Ahmadzadeh N, Shingu M, Nobunaga M, Tawara T. Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids. Inflammation. 1991; 15:497-503.
          135. 135.↵
            Koshihara Y, Isono T, Oda H, Karube S, Hayashi Y. Measurement of sulfidopeptide leukotrienes and their metabolism in human synovial fluid of patients with rheumatoid arthritis. Prostaglandins Leukot Essent Fatty Acids. 1988; 32:113-9.
          136. 136.↵
            Camp R, Jones RR, Brain S, Woollard P, Greaves M. Production of intraepidermal microabcesses by topical application of leukotriene B4. J Invest Dermatol. 1984; 82:202-4.
          137. 137.↵
            Brain SD, Camp RD, Dowd PM, Black AK, Woollard PM, Mallet AI, et al. Psoriasis and leukotriene B4 (Letter). Lancet. 1982; 2:762-3.
          138. 138.↵
            Ruzicka T, Simmet T, Peskar BA, Ring J. Skin levels of arachidonic acid-derived inflammatory mediators and histamine in atopic dermatitis and psoriasis. J Invest Dermatol. 1986; 86:105-8.
          139. 139.↵
            Fogh K, Herlin T, Kragballe K. Eicosanoids in acute and chronic psoriatic lesions: leukotriene B4, but not 12-hydroxy-eicosatetraenoic acid, is present in biologically active amounts in acute guttate lesions. J Invest Dermatol. 1989; 92:837-41.
          140. 140.↵
            Dowd PM, Greaves MW. Cutaneous responses to lipoxygenase products of arachidonic acid. Acta Derm Venereol Suppl (Stockh). 1985; 120:18-22.
          141. 141.↵
            Fauler J, Neumann C, Tsikas D, Frolich J. Enhanced synthesis of cysteinyl leukotrienes in psoriasis. J Invest Dermatol. 1992; 99:8-11.
          142. 142.↵
            Dias VC, Wallace JL, Parsons HG. Modulation of cellular phospholipid fatty acids and leukotriene B4 synthesis in the human intestinal cell (CaCo-2). Gut. 1992; 33:622-7.
          143. 143.↵
            Sharon P, Stenson WF. Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology. 1984; 86:453-60.
          144. 144.↵
            Hawthorne AB, Boughton-Smith NK, Whittle BJ, Hawkey CJ. Colorectal leukotriene B4 synthesis in vitro in inflammatory bowel disease: inhibition by the selective 5-lipoxygenase inhibitor BWA4C. Gut. 1992; 33:513-7.
          145. 145.↵
            Peskar BM, Dreyling KW, Peskar BA, May B, Goebell H. Enhanced formation of sulfidopeptide-leukotrienes in ulcerative colitis and Crohn's disease: inhibition by sulfasalazine and 5-aminosalicylic acid. Agents Actions. 1986; 18:381-3.
          146. 146.↵
            Lauritsen K, Laursen LS, Bukhave K, Rask-Madsen J. Effects of topical 5-aminosalicylic acid and prednisolone on prostaglandin E2 and leukotriene B4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis. Gastroenterology. 1986; 91:837-44.
          147. 147.↵
            Lauritsen K, Laursen LS, Bukhave K, Rask-Madsen J. In vivo profiles of eicosanoids in ulcerative colitis, Crohn's colitis, and Clostridium difficile colitis. Gastroenterology. 1988; 95:11-7.
          148. 148.↵
            Salmon JA, Garland LG. Leukotriene antagonists and inhibitors of leukotriene biosynthesis as potential therapeutic agents. Prog Drug Res. 1991; 37:9-90.
          149. 149.↵
            Musser JH, Kreft AF. 5-Lipoxygenase: properties, pharmacology, and the quinolinyl(bridged)aryl class of inhibitors. J Med Chem. 1992; 35:2501-24.
          150. 150.↵
            Ford-Hutchinson AW. Leukotriene antagonists and inhibitors as modulators of IgE-mediated reactions. Springer Semin Immunopathol. 1993; 15:37-50.
          151. 151.↵
            Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al 5-lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther. 1991; 256:929-37.
          152. 152.↵
            Prasit P, Belley M, Blouin M, Brideau C, Chan C, Charleson S, et al. A new class of leukotriene biosynthesis inhibitor: the development of MK-0591. J Lipid Mediat. 1993; 6:239-44.
          153. 153.↵
            Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. N Engl J Med. 1990; 323:1736-9.
          154. 154.↵
            Margolskee D, Bodman S, Dockhorn R, Israel E, Kemp J, Mansmann H, et al. The therapeutic effects of MK-571, a potent and selective leukotriene (LT) D4 receptor antagonist, in patients with chronic asthma (Abstract). J Allergy Clin Immunol. 1991; 87:309.
          155. 155.↵
            Margolskee D, Friedman B, Williams V, Botto A, Noonan N, Altman L, et al. The therapeutic effects of MK-0679, a selective leukotriene D4 receptor antagonist, in patients with chronic asthma (Abstract). 8th International Conference on Prostaglandins and Related Compounds. Montreal, Canada: July 26-31,1992; 163.
          156. 156.↵
            Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinyl-leukotriene receptor antagonist ICI 204,219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991; 337:690-4.
          157. 157.↵
            Richards IM, Griffin RL, Oostveen JA, Morris J, Wishka DG, Dunn CJ. Effect of the selective leukotriene B4 antagonist U-75302 on antigen-induced bronchopulmonary eosinophilia in sensitized guinea pigs. Am Rev Respir Dis. 1989; 140:1712-6.
          158. 158.↵
            Friedman BS, Bel EH, Buntinx A, Tanaka W, Han YH, Shingo S, et al. Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. Am Rev Respir Dis. 1993; 147:839-44.
          159. 159.↵
            Israel E, Dermarkarian R, Rosenberg M, Sperling R, Taylor G, Rubin P, et al. The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. N Engl J Med. 1990; 323:1740-4.
          160. 160.↵
            Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993; 119:1059-66.
          161. 161.↵
            Christie PE, Smith CM, Lee TH. The potent and selective sulfidopeptide leukotriene antagonist, SK&F 104353, inhibits aspirin-induced asthma. Am Rev Respir Dis. 1991;144:957-8.
          162. 162.↵
            Israel E, Fischer AR, Rosenberg MA, Lilly CM, Callery JC, Shapiro J, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Am Rev Respir Dis. 1993; 148:1447-51.
          163. 163.↵
            Knapp HR. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med. 1990; 323:1745-8.
          164. 164.↵
            Howarth PH, Harrison K, Lau L, Dube L, Cohn J. The influence of the 5-lipoxygenase inhibitor A-78773 on the nasal response to allergen in rhinitis (Abstract). J Allergy Clin Immunol. 1994; 93:297.
          165. 165.↵
            Nagai H, Kitagaki K, Miura T, Shimazawa T, Koda A. Effect of a newly synthesized leukotriene antagonist, (E)-2,2-diethyl-3′-2-2-(4-isopropyl) thiazolyl ethenyl succnanilic acid (MCI-826), on immunological liver injury and nephritis in mice. Prostaglandins Leukot Essent Fatty Acids. 1992; 47:51-7.
          166. 166.↵
            Weinblatt ME, Kremer JM, Coblyn JS, Helfgott S, Maier AL, Petrillo G, et al. Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis. J Rheumatol. 1992; 19:1537-41.
          167. 167.↵
            Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME. Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum. 1992; 35:376-84.
          168. 168.↵
            Elmgreen J, Ahnfelt-Ronne I, Nielsen OH. Inhibition of human neutrophils by auranofin: chemotaxis and metabolism of arachidonate via the 5-lipoxygenase pathway. Ann Rheum Dis. 1989; 48:134-8.
          169. 169.↵
            Black AK, Camp RD, Mallet AI, Cunningham FM, Hofbauer M, Greaves MW. Pharmacologic and clinical effects of lonapalene (RS 43179), a 5-lipoxygenase inhibitor, in psoriasis. J Invest Dermatol. 1990; 95:50-4.
          170. 170.↵
            Degreef H, Dockx P, De Doncker P, De Beule K, Cauwenbergh G. A double-blind vehicle-controlled study of R 68 151 in psoriasis: a topical 5-lipoxygenase inhibitor. J Am Acad Dermatol. 1990; 22:751-5.
          171. 171.↵
            de Jong EM, van Vlijmen IM, Scholte JC, Buntinx A, Friedman B, Tanaka W, et al. Clinical and biochemical effects of an oral leukotriene biosynthesis inhibitor (MK886) in psoriasis. Skin Pharmacol. 1991; 4:278-85.
          172. 172.↵
            Fretland DJ, Widomski D, Tsai BS, Zemaitis JM, Levin S, Djuric SW, et al. Effect of the leukotriene B4 receptor antagonist SC-41930 on colonic inflammation in rat, guinea pig and rabbit. J Pharmacol Exp Ther. 1990; 255:572-6.
          173. 173.↵
            Wallace JL, Keenan CM. An orally active inhibitor of leukotriene synthesis accelerates healing in rat model of colitis. Am J Physiol. 1990; 258:G527-34.
          174. 174.↵
            Collawn C, Rubin P, Perez N, Bobadilla J, Cabrera G, Reyes E, et al. Phase II study of the safety and efficacy of a 5-lipoxygenase inhibitor in patients with ulcerative colitis. Am J Gastroenterol. 1992; 87:342-6.
          175. 175.
            Corey EJ, Munroe JE. Irreversible inhibition of prostaglandin and leukotriene biosynthesis from arachidonic acid by 11,12-dehydro- and 5,6-dehydroarachidonic acids, respectively. Journal of the American Chemical Society. 1982; 104:1752-4.
          176. 176.
            Hui KP, Lotvall J, Chung KF, Barnes PJ. Attenuation of inhaled allergen-induced airway microvascular leakage and airflow obstruction in guinea pigs by 5-lipoxygenase inhibitor (A-63162). Am Rev Respir Dis. 1991; 143:1015-9.
          177. 177.
            Bell RL, Bouska J, Young PR, Lanni C, Machinist J, Malo PE, et al. The properties of A-69412: a small hydrophilic 5-lipoxygenase inhibitor. Agents Actions. 1993; 38:178-87.
          178. 178.
            Bell RL, Brooks DW, Young PR, Lanni C, Stewart AO, Bouska J, et al. A-78773: a selective, potent 5-lipoxygenase inhibitor. J Lipid Mediat. 1993; 6:259-64.
          179. 179.
            Ashida Y, Saijo T, Kuriki H, Makino H, Terao S, Maki Y. Pharmacological profile of AA-861, a 5-lipoxygenase inhibitor. Prostaglandins. 1983; 26:955-72.
          180. 180.
            Wegner CD, Gundel RH, Abraham WM, Schulman ES, Kontny MJ, Lazer ES, et al. The role of 5-lipoxygenase products in preclinical models of asthma. J Allergy Clin Immunol. 1993; 91:917-29.
          181. 181.
            Higgs GA, Flower RJ, Vane JR. A new approach to anti-inflammatory drugs. Biochem Pharmacol. 1979; 28:1959-61.
          182. 182.
            Mathews WR, Murphy RC. Inhibition of leukotriene biosynthesis in mastocytoma cells by diethylcarbamazine. Biochem Pharmacol. 1982; 31:2129-32.
          183. 183.
            Bokoch GM, Reed PM. Evidence for inhibition of leukotriene A4 synthesis by 5,8,11,14-eicosatetraynoic acid in guinea pig polymorphonuclear leukocytes. J Biol Chem. 1981; 256:4156-9.
          184. 184.
            Vanderhoek JY, Bryant RW, Bailey JM. Inhibition of leukotriene biosynthesis by the leukocyte product 15-hydroxy-5,8,11,13-eicosatetraenoic acid. J Biol Chem. 1980; 255:10064.
          185. 185.
            McMillan RM, Spruce KE, Crawley GC, Walker ER, Foster SJ. Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase. Br J Pharmacol. 1992; 107:1042-7.
          186. 186.
            Koshishara Y, Murota S, Petasis NA, Nicolaou KC. Selective inhibition of 5-lipoxygenase by 5,6-methanoleukotriene A4, a stable analogue of leukotriene A4. FEBS Lett. 1982; 143:13-6.
          187. 187.
            Honn KV, Dunn JR. Nafazatrom (Bay g 6575) inhibition of tumor cell lipoxygenase activity and cellular proliferation. FEBS Lett. 1982; 139:65-8.
          188. 188.
            Hamberg M. On the formation of thromboxane B2 and 12 L-hydroxy-5,8,10,14-eicosatetraenoic acid (12ho-20:4) in tissues from the guinea pig. Biochim Biophys Acta. 1976; 431:651-4.
          189. 189.
            Bach MK, Brashler JR, Smith HW, Fitzpatrick FA, Sun FF, McGuire JC. 6,9-deepoxy-6,9-(phenylimino)-delta6,8- prostaglandin I1, (U-60,257), a new inhibitor of leukotriene C and D synthesis: in vitro studies. Prostaglandins. 1982; 23:759-71.
          190. 190.
            Lehman PA, Henderson WR Jr. Retinoid-induced inhibition of eosinophil LTC4 production. Prostaglandins. 1990; 39:569-77.
          191. 191.
            Weir MR, Li XW, Gomolka D, Peppler R, O'Bryan-Tear CG, Moran MA. The immunosuppressive properties of enisoprost and a 5-lipoxygenase inhibitor (SC-45662). Transplantation. 1991; 52:1053-7.
          192. 192.
            Hatzelmann A, Fruchtmann R, Mohrs KH, Raddatz S, Muler-Peddinghaus R. Mode of action of the new selective leukotriene synthesis inhibitor BAY X 1005([R]-2-(4-[quinolin-2-yl-methoxy]phenyl)-2-cyclopentyl acetic acid) and structurally related compounds. Biochem Pharmacol. 1993; 45:101-11.
          193. 193.
            Anderson G, Fennessy M. Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig. Br J Pharmacol. 1988; 94:1115-22.
          194. 194.
            Grimes D, Sturm RJ, Marinari LR, Carlson RP, Berkenkopf JW, Musser JH, et al. WY-50,295 tromethamine, a novel, orally active 5-lipoxygenase inhibitor: biochemical characterization and antiallergic activity. Eur J Pharmacol. 1993; 236:217-28.
          195. 195.
            Sugasawa T, Morooka S. Effect of BRL-35135 on LTB4-induced guinea pig eosinophil chemotaxis. Agents Actions. 1992; 37:232-7.
          196. 196.
            Jackson WT, Boyd RJ, Froelich LL, Gapinski DM, Mallett BE, Sawyer JS. Design, synthesis, and pharmacological evaluation of potent xanthone dicarboxylic acid leukotriene B4 receptor antagonists. J Med Chem. 1993; 36:1726-34.
          197. 197.
            Marder P, Schultz RM, Spaethe SM, Sofia MJ, Herron DK. Flow cytometric evaluation of the effects of leukotriene B4 receptor antagonists (LY255283 and SC-41930) on calcium mobilization and integrin expression of activated human neutrophils. Prostaglandins Leukot Essent Fatty Acids. 1992; 46:265-70.
          198. 198.
            Kishikawa K, Tateishi N, Maruyama T, Seo R, Toda M, Miyamoto T. ONO-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions. Prostaglandins. 1992; 44:261-75.
          199. 199.
            Villani-Price D, Yang DC, Walsh RE, Fretland DJ, Keith RH, Kocan G, et al. Multiple actions of the leukotriene B4 receptor antagonist SC-41930. J Pharmacol Exp Ther. 1992; 260:187-91.
          200. 200.
            Fretland DJ, Widomski DL, Anglin CP, Penning TD, Yu S, Djuric SW. Leukotriene B4-induced granulocyte trafficking in guinea pig dermis. Effect of second-generation leukotriene B4 receptor antagonists, SC-50605 and SC-51146. Inflammation. 1993; 17:353-60.
          201. 201.
            Augstein J, Farmer JB, Lee TB, Sheard P, Tattersall ML. Selective inhibitor of slow reacting substance of anaphylaxis. Nature New Biol. 1973; 245:215-7.
          202. 202.
            Phillips GD, Rafferty P, Robinson C, Holgate ST. Dose-related antagonism of leukotriene D4induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects. J Pharmacol Exp Ther. 1988; 246:732-8.
          203. 203.
            Jones TR, Zamboni R, Belley M, Champion E, Charette L, Ford-Hutchinson AW, et al. Pharmacology of L-660,711 (MK-571): a novel potent and selective leukotriene D4 receptor antagonist. Can J Physiol Pharmacol. 1989; 67:17-28.
          204. 204.
            Nakai H, Konno M, Kosuge S, Sakuyama S, Toda M, Arai Y, et al. New potent antagonists of leukotriene C4 and D4. 1. Synthesis and structure-activity relationships. J Med Chem. 1988; 31:84-91.
          205. 205.
            Hay DW, Muccitelli RM, Tucker SS, Vickery-Clark LM, Wilson KA, Gleason JG, et al. Pharmacologic profile of SK&F 104353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways. J Pharmacol Exp Ther. 1987;243:474-81.
          206. 206.
            Hand JM, Auen MA, Chang J, Englebach IM. Prevention and reversal of aerosol LTD4-induced changes in guinea pig pulmonary mechanics by Wy-48252, an orally active LTD4/E4 receptor antagonist. Int Arch Allergy Appl Immunol. 1989; 89:78-82.
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