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.

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    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.

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