Extending the understanding of leukotrienes in asthma

Current Opinion in Allergy and Clinical Immunology

Volumn 3, Issue 1, 2003, Pages 57-63

  Coffey, Michael ^a   Peters Golden, Marc ^a,b  

^a UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

^b 6301 MSRB III ^*  (United States)

Author keywords

5 Lipoxygenase; Cysteinyl LT receptors; Cytokines; Leukotriene C4 synthase

Indexed keywords

ARACHIDONATE 5 LIPOXYGENASE; CYTOKINE; INTERLEUKIN 13; INTERLEUKIN 4; LEUKOTRIENE C4 SYNTHASE; LEUKOTRIENE RECEPTOR; PEPTIDOLEUKOTRIENE;

ALLERGIC DISEASE; ASTHMA; CHRONIC DISEASE; ENZYME POLYMORPHISM; HUMAN; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; REVIEW; TH2 CELL; UPREGULATION; VIRUS INFECTION;

ADULT; ARACHIDONATE 5-LIPOXYGENASE; ASTHMA; CHILD; GLUTATHIONE TRANSFERASE; HUMANS; LEUKOTRIENES; MEMBRANE PROTEINS; POLYMORPHISM, GENETIC; RECEPTORS, LEUKOTRIENE;

EID: 0037311304     PISSN: 15284050     EISSN: None     Source Type: Journal    
DOI: 10.1097/00130832-200302000-00010     Document Type: Review

References (55)

1. Drazen J, Israel E, O'Byrne P. Treatment of asthma with drugs modifying the leukotriene pathway. N Eng J Med 1999; 340:197-206.
2. Hsieh FH, Lam BK, Penrose JF, et al. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4. J Exp Med 2001; 193:123-133.
3. Cowburn AS, Holgate ST, Sampson AP. IL-5 increases expression of 5-lipoxygenase-activating protein and translocates 5-lipoxygenase to the nucleus in human blood eosinophils. J Immunol 1999; 163:456-465.
4. McColl S, Krump E, Naccache P, et al. Granulocyte-macrophage colonystimulating factor increases the synthesis of Leukotriene B4 by human neutrophils in response to platelet-activating factor. J Immunol 1991; 146:1204-1211.
5. Brock T, McNish R, Coffey M, et al. Effect of granulocyte-macrophage colony-stimulating factor on eicosanoid production by mononuclear phagocytes. J Immunol 1996; 156:2522-2527.
6. Riddick C, Serio K, Hodulik C, et al. TGF-beta increases leukotriene C4 synthase expression in the monocyte-like cell line, THP-1. J Immunol 1999; 162:1101-1107.
7. Lord G, Matarese G, Howard J, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394:897-901.
8. Mancuso P, Gottschalk A, Phare S, et al. Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol 2002; 168:4018-4024. The adipocyte-derived hormone leptin, which is secreted in correlation with total body fat stores, regulates leukotriene synthesis.
9. Litonjua A, Sparrow D, Celedon J, et al. Association of body mass index with the development of methacholine airway hyperresponsiveness in men: the Normative Aging Study. Thorax 2002; 57:581-585.
10. Drazen J, O'Brien J, Sparrow D, et al. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis 1992; 146:104-108.
11. Lee T, Christie P. Leukotrienes and aspirin induced asthma. Thorax 1993; 48:1189-1190.
12. Seymour M, Rak S, Aberg D, et al. Leukotriene and prostanoid pathway enzymes in bronchial biopsies of seasonal allergic asthmatics. Am J Respir Crit Care Med 2001; 164:2051-2056. A natural experiment, comparing subjects before-season and in-season, demonstrated increased expression of the enzymes involved in 5-lipoxygenase metabolism in association with increased airway obstruction upon antigen exposure.
13. Lee E, Robertson T, Smith J, et al. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med 2000; 161:1881-1886.
14. In K, Asano K, Beier D, et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 1997; 99:1130-1137.
15. Drazen J, Yandava C, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999; 22:168-170.
16. Fowler S, Hall I, Wilson A, et al. 5-Lipoxygenase polymorphism and in-vivo response to leukotriene receptor antagonists. Eur J Clin Pharmacol 2002; 58:187-190. This is an interesting observation showing that heterozygous mutations of the 5-lipoxygenase gene promoter had no difference in bronchodilator response or hyperresponsiveness compared with the patients with a homozygous wild type genotype.
17. Sanak M, Pierzchalska M, Bazan-Socha S, et al. Enhanced expression of the leukotriene C(4) synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 2000; 23:290-296.
18. Van Sambeek R, Stevenson D, Baldasaro M, et al. 5′ flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States. J Allergy Clin Immunol 2000; 106:72-76.
19. Sampson A, Siddiqui S, Buchanan D, et al. Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000; 55:S28-S31.
20. Kawagishi Y, Mita H, Taniguchi M, et al. Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J Allergy Clin Immunol 2002; 109:936-942. This paper confirms the increased frequency of leukotriene C4 synthase polymorphisms in aspirin intolerant asthma in a Japanese population. However, it disputes the correlation between the polymorphism and leukotriene C4 synthase activity in eosinophils, calling into question whether the mechanism involves increased cysteinyl leukotriene synthesis.
21. Serio K, Hodulik C, Bigby T. Sp1 and Sp3 function as key regulators of leukotriene C(4) synthase gene expression in the monocyte-like cell line, THP-1. Am J Respir Cell Mol Biol 2000; 23:234-240.
22. Torres-Galvan M, Ortega N, Sanchez-Garcia F, et al. LTC4-synthase A-444C polymorphism: lack of association with NSAID-induced isolated periorbital angioedema in a Spanish population. Ann Allergy Asthma Immunol 2001; 87:506-510. These investigators cast further doubt on the association between the A→C transversion in the leukotriene C4 synthase promoter and non-steroidal anti-inflammatory drug-induced edema in a Spanish population.
23. Lynch K, O'Neill G, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999; 399:789-793.
24. Martin V, Sawyer N, Stocco R, et al. Molecular cloning and functional characterization of murine cysteinyl-leukotriene 1 (CysLT(1)) receptors. Biochem Pharmacol 2001; 62:1193-1200.
25. Izumi T, Yokomizo T, Obinata H, et al. Leukotriene receptors: classification, gene expression, and signal transduction. J Biochem 2002; 132:1-6.
26. Thivierge M, Stankova J, Rola-Pleszczynski M. IL-13 and IL-4 up-regulate cysteinyl leukotriene 1 receptor expression in human monocytes and macrophages. J Immunol 2001; 167:2855-2860. Th2 cytokines augmented expression and function of cysLT1 on human monocytes and macrophages. Therefore, in addition to increasing cysLT synthesis, Th2 cytokines augment cysLT action by increasing cysLT1 expression and function.
27. Nag S, Lamkhioued B, Renzi P. Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway. Am J Respir Crit Care Med 2002; 165:1540-1545. Airway responsiveness to leukotriene D4 was increased by pretreatment with interleukin-2 in ovalbumin-sensitized rats. The mechanism is mediated by cysLT1 as montelukast blocked this increased late airway response. In addition, cysLT 1 activity led to a predominant Th2 cytokine phenotype.
28. Amrani Y, Moore P, Hoffman R, et al. Interferon-gamma modulates cysteinyl leukotriene receptor-1 expression and function in human airway myocytes. Am J Respir Crit Care Med 2001; 164:2098-2101. The Th1 cytokine interferon-γ upregulates expression of cysLT1 on human smooth muscle cells and increases leukotriene D4-induced muscle contraction. Elaboration of interferon-γ by viral infection may explain their mechanism of triggering asthma attacks.
29. Heise C, O'Dowd B, Figueroa D, et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000; 275:30531-30536.
30. Hui Y, Yang G, Galczenski H, et al. The murine cysteinyl leukotriene 2 (CysLT2) receptor. CDNA and genomic cloning, alternative splicing, and in vitro characterization. J Biol Chem 2001; 276:47489-47495. This is the first description of molecular cloning of the murine cysLT2 receptor. The relative expression in various tissues is described as well as the rank order of ligand potencies.
31. Mita H, Hasegawa M, Saito H, et al. Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils. Clin Exp Allergy 2001; 31:1714-1723. These investigators describe that cysLT2 messenger RNA expression was more abundant on eosinophils than cysLT1. If cysLT2 protein expression is abundant in eosinophils, this receptor may mediate some of the effects of cysLT in eosinophils.
32. Dahlen S. Pharmacological characterization of leukotriene receptors. Am J Respir Crit Care Med 161:S41-S45.
33. Gauvreau G, Parameswaran K, Watson R, et al. Inhaled leukotriene E(4), but not leukotriene D(4), increased airway inflammatory cells in subjects with atopic asthma. Am J Respir Crit Care Med 2001; 164:1495-1500. Leukotriene E4, at doses that caused comparable degrees of bronchoconstriction caused more prominent eosinophil recruitment than did leukotriene D4 suggesting that an unrecognized non-cysLT1 non-cysLT2 receptor may be responsible.
34. Peters-Golden M, Brock T. Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets. FEBS Lett 2001; 487:323-326.
35. Bandeira-Melo C, Phoofolo M, Weller P. Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils. J Biol Chem 2001; 276:22779-22787.
36. Bandeira-Melo C, Woods L, Phoofolo M, et al. Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion. J Exp Med 2002; 196:841-850. This report describes further evidence of another cysLT receptor. Leukotriene C4 may regulate the secretion of interleukin-4 from eosinophils through a non-cysLT1 or cysLT2 receptor. This effect of leukotriene C4 may be through an intracellular seven-transmembrane receptor. These findings may explain why this eicosanoid is synthesized deep within the cell.
37. Tohda Y, Nakahara H, Kubo H, et al. Effects of ONO-1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma. Clin Exp Allergy 1999; 29:1532-1536.
38. Underwood D, Osborn R, Newsholme S, et al. Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody. Am J Respir Crit Care Med 1996; 154:850-857.
39. Henderson WJ, Tang L, Chu S, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med 2002; 165:108-116. A role for cysLT in the pathogenesis of chronic airway inflammation and development of subepithelial fibrosis in an antigen-sensitized/challenged mouse model is described. Airway remodeling in chronic asthma may be responsive to anti-leukotriene therapy.
40. Peters-Golden M, Bailie M, Marshall T, et al. Protection from pulmonary fibrosis in leukotriene-deficient mice. Am J Respir Crit Care Med 2002; 165:229-235. 5-Lipoxygenase knock-out mice treated with intratracheal bleomycin were relatively protected from the development of pulmonary fibrosis. Interestingly, these animals had higher levels of the antifibrotic cytokine interferon-γ.
41. Spada C, Nieves A, Krauss A, et al. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 1994; 55:183-191.
42. Nagata M, Saito K, Tsuchiya K, et al. Leukotriene D4 upregulates eosinophil adhesion via the cysteinyl leukotriene 1 receptor. J Allergy Clin Immunol 2002; 109:676-680. CysLTs, as well as attracting and activating eosinophils, have been shown to increase their adhesiveness to intercellular adhesion molecule.
43. Braccioni F, Dorman S, O'Byrne P, et al. The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol 2002; 110:96-101. Leukotriene D4 stimulates growth of eosinophilic precursors from bone marrow and peripheral blood stimulated with cytokines. This report provides an explanation for the finding that anti-LT drugs suppress eosinophil numbers in the peripheral blood as well as in the lung.
44. Pizzichini E, Leff J, Reiss T, et al. Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999; 14:12-18.
45. Wang C, Du T, Xu L, et al. Role of leukotriene D4 in allergen-induced increases in airway smooth muscle in the rat. Am Rev Respir Dis 1993; 148:413-417.
46. Baud L, Perez J, Denis M, et al. Modulation of fibroblast proliferation by sulfidopeptide leukotrienes: effect of indomethacin. J Immunol 1987; 138:1190-1195.
47. Panetteirri R, Tan E, Ciocca V, et al. Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 1998; 19:453-461.
48. Phan S, McGarry B, Loeffler K, et al. Binding of leukotriene C4 to rat lung fibroblasts and stimulation of collagen synthesis in vitro. Biochemistry 1988; 27:2846-2853.
49. Parameswaran K, Cox G, Radford K, et al. Cysteinyl leukotrienes promote human airway smooth muscle migration. Am J Respir Crit Care Med 2002; 166:738-742. Leukotriene E4 treatment augmented the directional migratory response of human smooth muscle cells to platelet-derived growth factor via a phosphatidylinositol-3 kinase-dependent pathway.
50. Volovitz B, Welliver R, De Castro G, et al. The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res 1988; 24:504-507.
51. Seymour ML, Gilby N, Bardin PG, et al. Rhinovirus infection increases 5-lipoxygenase and cyclooxygenase-2 in bronchial biopsy specimens from nonatopic subjects. J Infect Dis 2002; 185:540-544. Experimental infection with rhinovirus resulted in increased cysLT levels in bronchial biopsies of non-atopic subjects. There was increased expression of 5. lipoxygenase and FLAP-positive cells. This demonstrates a mechanism by which viral infections may trigger asthma attacks.
52. Wedde-Beer K, Hu C, Rodriguez M, et al. Leukotrienes mediate neurogenic inflammation in lungs of young rats infected with respiratory syncytial virus. Am J Physiol Lung Cell Mol Physiol 2002; 282:L1143-L1150. This report demonstrates that inflammation induced by viral infections is cysLT mediated. Leukotriene inhibitors may have a role in the treatment of viral-induced asthma.
53. Ng D, Law A, Chau K, et al. Use of montelukast in the treatment of early childhood wheezing from clinical experience with three cases. Respirology 2000; 5:389-392.
54. Montuschi P, Barnes P. Analysis of exhaled breath condensate for monitoring airway inflammation. Trends Pharmacol Sci 2002; 23:232-237.
55. Antczak A, Montuschi P, Kharitonov S, et al. Increased exhaled cysteinylleukotrienes and 8-isoprostane in aspirin-induced asthma. Am J Respir Crit Care Med 2002; 166:301-306. This technique describes airway secretions sampled non-invasively by exhaled breath condensate, revealing increased cysLT in asthmatics with highest levels in aspirin intolerant asthma. This method of measuring leukotriene biosynthesis, if widely applicable, may help predict an individual's likelihood of responding to leukotriene modifiers.