Current Allergy and Asthma Reports

, Volume 7, Issue 2, pp 126–133

Leukotriene synthesis inhibitors versus antagonists: The pros and cons

Article

Abstract

It has been recognized for many years that leukotrienes play an important role in mediating various effects of the allergic reaction. Recent evidence has shown that they play a role in other diseases. Leukotrienes can be separated into the fairly well-characterized cysteinyl leukotrienes and the less well-characterized leukotriene B4. Effects of the leukotrienes are mediated through receptors that are expressed on a variety of cell types and can be modulated based on the inflammatory environment present. The pharmaceutical industry has long been interested in blocking leukotriene action. As such, two approaches have been developed that led to drugs approved for treating allergic disease. The most widely used class is the cysteinyl type 1 receptor antagonists, which block binding of the cysteinyl leukotrienes to the cell. The second class is an inhibitor of the 5-lipoxygenase enzyme that prevents synthesis of both the cysteinyl leukotrienes and leukotriene B4. This review focuses on the role that leukotrienes play in various diseases, with the emphasis on allergic diseases, and considers the rationale for choosing either a leukotriene antagonist or synthesis inhibitor as a treatment option.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Yopp AC, Randolph GJ, Bromberg JS: Leukotrienes, sphingolipids, and leukocyte trafficking. J Immunol 2003, 171:5–10.PubMedGoogle Scholar
  2. 2.
    Christmas P, Weber BM, McKee M: Membrane localization and topology of leukotriene C4 synthase. J Biol Chem 2002, 277:28902–28908.PubMedCrossRefGoogle Scholar
  3. 3.
    Lynch KR, O’Neill GP, Liu Q, et al.: Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999, 399:789–793.PubMedCrossRefGoogle Scholar
  4. 4.
    Heise CE, O’Dowd BF, Figueroa DJ, et al.: Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000, 275:30531–30536.PubMedCrossRefGoogle Scholar
  5. 5.
    Figueroa DJ, Breyer R, Defoe S, et al.: Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Crit Care Med 2001, 163:226–233.Google Scholar
  6. 6.
    Figueroa DJ, Borish L, Baramki D, et al.: Expression of cysteinyl leukotriene synthetic and signaling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin Exp Allergy 2003, 33:1380–1388.PubMedCrossRefGoogle Scholar
  7. 7.
    Walch L, Norel X, Back M, et al.: Pharmacologic evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle. Br J Pharmacol 2002, 137:1339–1345.PubMedCrossRefGoogle Scholar
  8. 8.
    Ciana P, Fumagalli M, Trincavelli ML, et al.: The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO Journal 2006, 25:4615–4627.PubMedCrossRefGoogle Scholar
  9. 9.
    Sousa AR, Parikh A, Scadding G, et al.: Leukotriene-receptor expression on nasal mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N Engl J Med 2002, 347:1493–1499.PubMedCrossRefGoogle Scholar
  10. 10.
    Sjostrom M, Johansson A, Schroder O, et al.: Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 2003, 23:e37–e41.PubMedCrossRefGoogle Scholar
  11. 11.
    James AJ, Penrose JF, Cazaly AM, et al.: Human bronchial fibroblasts express the 5-lipoxygenase pathway. Respir Research 2006, 7:102.CrossRefGoogle Scholar
  12. 12.
    Steinke JW, Crouse CD, Bradley D, et al.: Characterization of interleukin-4 stimulated nasal polyp fibroblasts. Am J Respir Cell Mol Biol 2004, 30:212–219.PubMedCrossRefGoogle Scholar
  13. 13.
    Tager AM, Luster AD: BLT1 and BLT2: the leukotriene B4 receptors. Prostaglandins Leukot Essent Fatty Acids 2003, 69:123–134.PubMedCrossRefGoogle Scholar
  14. 14.
    Yokomizo T, Izumi T, Shimizu T: Co-expression of LTB4 receptors in human mononuclear cells. Life Sciences 2001, 68:2207–2212.PubMedCrossRefGoogle Scholar
  15. 15.
    Mellor EA, Frank M, Soler D, et al.: Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: functional distinction from CysLT1R. Proc Nat Acad Sci U S A 2003, 100:11589–11593.CrossRefGoogle Scholar
  16. 16.
    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.PubMedGoogle Scholar
  17. 17.
    Thivierge M, Doty M, Johnson J, et al.: IL-5 up-regulates cysteinyl leukotriene 1 receptor expression in HL-60 cells differentiated into eosinophils. J Immunol 2000, 165:5221–5226.PubMedGoogle Scholar
  18. 18.
    Qui H, Johansson AS, Sjostrom M, et al.: Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4. Proc Natl Acad Sci U S A 2006, 103:6913–6918.CrossRefGoogle Scholar
  19. 19.
    Bjorck T, Dahlen SE: Leukotrienes and histamine mediate IgE-dependent contractions of human bronchi: pharmacological evidence obtained with tissues from asthmatic and non-asthmatic subjects. Pulm Pharmacol 1993, 6:87–96.PubMedCrossRefGoogle Scholar
  20. 20.
    Rasmussen JB, Margolskee DJ, Eriksson LO, et al.: Leukotriene (LT) D4 is involved in antigen-induced asthma: a study with the LTD4 receptor antagonist, MK-571. Ann NY Acad Sci 1991, 629(436).Google Scholar
  21. 21.
    Shirasaki H, Kanaizumi E, Watanabe K, et al.: Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa. Clin Exp Allergy 2002, 32:1007–1012.PubMedCrossRefGoogle Scholar
  22. 22.
    Arm JP, O’Hickey S, Spur BW, Lee TH: Airway responsiveness to histamine and leukotriene E4 in subjects with aspirin-induced asthma. Am Rev Respir Dis 1989, 140:148–153.PubMedGoogle Scholar
  23. 23.
    Fauler J, Neumann C, Tsikas D, Frolich J: Enhanced synthesis of cysteinyl leukotrienes in atopic dermatitis. Br J Dermatol 1993, 128:627–630.PubMedCrossRefGoogle Scholar
  24. 24.
    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, 86:105–108.PubMedCrossRefGoogle Scholar
  25. 25.
    Di Lorenzo G, Pacor ML, Vignola AM, et al.: Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients. Allergy 2002, 57:1180–1186.PubMedCrossRefGoogle Scholar
  26. 26.
    Spanbroek R, Grabner R, Lotzer K, et al.: Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A 2003, 100:1238–1243.PubMedCrossRefGoogle Scholar
  27. 27.
    Cipollone F, Mezzetti A, Fazia ML, et al.: Association between 5-lipoxygenase expression and plaque instability in humans. Arterioscler Thromb Vasc Biol 2005, 25:1665–1670.PubMedCrossRefGoogle Scholar
  28. 28.
    Dwyer JH, Allayee H, Dwyer KM, et al.: Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004, 350:29–37.PubMedCrossRefGoogle Scholar
  29. 29.
    Montuschi P, Kharitonov SA, Ciabattoni G, Barnes PJ: Exhaled leukotrienes and prostaglandins in COPD. Thorax 2003, 58:585–588.PubMedCrossRefGoogle Scholar
  30. 30.
    Michel L, Dubertret L: Leukotriene B4 and platelet-activating factor in human skin. Arch Dermatol Res 1992, 284:S12–S17.PubMedCrossRefGoogle Scholar
  31. 31.
    Reilly DM, Parslew R, Sharpe GR, et al.: Inflammatory mediators in normal, sensitive and diseased skin types. Acta Derm Venereol 2000, 80:171–174.PubMedCrossRefGoogle Scholar
  32. 32.
    Coreno A, Skowronski M, Kotaru C, McFadden ER: Comparative effects of long-acting b2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma. J Allergy Clin Immunol 2000, 106:500–506.PubMedCrossRefGoogle Scholar
  33. 33.
    Gaddy JN, Margolskee DJ, Bush RK, et al.: Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. Am Rev Respir Dis 1992, 146:358–363.PubMedGoogle Scholar
  34. 34.
    Bisgaard H, Zielen S, Garcia-Garcia ML, et al.: Montelukast reduces asthma exacerbations in 2-to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005, 171:315–322.PubMedCrossRefGoogle Scholar
  35. 35.
    Knapp HR: Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 1990, 323:1745–1748.PubMedCrossRefGoogle Scholar
  36. 36.
    van Adelsberg J, Philip G, LaForce CF, et al.: Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2003, 90:214–222.PubMedGoogle Scholar
  37. 37.
    Braccioni F, Dorman SC, O’Byrne PM, et al.: The effects 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.PubMedCrossRefGoogle Scholar
  38. 38.
    Pizzichini E, Leff JA, Reiss TF, et al.: Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J 1999, 14:12–18.PubMedCrossRefGoogle Scholar
  39. 39.
    Steinke JW, Bradley D, Arango P, et al.: Cysteinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: Importance to eosinophilia and asthma. J Allergy Clin Immunol 2003, 111:342–349.PubMedCrossRefGoogle Scholar
  40. 40.
    Parnes SM, Churna AV: Acute effects of antileukotrienes on sinonasal polyposis and sinusitis. ENT Journal 2000, 79:18–21.Google Scholar
  41. 41.
    Parnes SM: The role of leukotriene inhibitors inpatients with paranasal sinus disease. Curr Opin Otolaryngol Head Neck Surg 2003, 11:184–191.PubMedCrossRefGoogle Scholar
  42. 42.
    Dirienzo L, Artuso A, Corqua N: Antileukotrienes in the prevention of postoperative recurrence of nasal polyposis in ASA syndrome. Acta Otorhinolaryngol Ital 2000, 20:336–342.Google Scholar
  43. 43.
    Grundmann T, Topfner M: Treatment of ASS-associated polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist-a prospective drug study on its anti-inflammatory effects. Laryngorhinootologie 2001, 80:576–582.PubMedCrossRefGoogle Scholar
  44. 44.
    Dahlen B, Nizankowska E, Szczeklik A: Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998, 157:1187–1194.PubMedGoogle Scholar
  45. 45.
    Carucci JA, Washenik K, Weinstein A, et al.: The leukotriene antagonist zafirlukast as a therapeutic agent for atopic dermatitis. Arch Dermatol 1998, 134:785–786.PubMedCrossRefGoogle Scholar
  46. 46.
    Woodmansee DP, Simon RA: A pilot study examining the role of zileuton in atopic dermatitis. Ann Allergy Asthma Immunol 1999, 83:548–552.PubMedCrossRefGoogle Scholar
  47. 47.
    Bensch G, Borish L: Leukotriene modifiers in chronic urticaria. Ann Allergy Asthma Immunol 1999, 83:348.PubMedGoogle Scholar
  48. 48.
    Erbagci Z: The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol 2002, 110:484–488.PubMedCrossRefGoogle Scholar
  49. 49.
    Di Lorenzo G, Pacor ML, Mansueto P, et al.: Randomized placebo-controlled trial comparing desloratadine and montelukast in monotherapy and desloratadine plus montelukast in combined therapy for chronic idiopathic urticaria. J Allergy Clin Immunol 2004, 114:619–625.PubMedCrossRefGoogle Scholar
  50. 50.
    Panettieri RA, Tan EML, 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.PubMedGoogle Scholar
  51. 51.
    Pederson KE, Bochner BS, Undem BJ: Cysteinyl leukotrienes induce P-selectin expression in human endothelial cells via a non-CysLT1 receptor-mediated mechanism. J Pharmacol Exp Ther 1997, 281:655–662.Google Scholar
  52. 52.
    Zouboulis CC, Nestoris S, Adler YD, et al.: A new concept for acne therapy: a pilot study with zileuton, an oral 5-lipoxygenase inhibitor. Arch Dermatol 2003, 139:668–670.PubMedCrossRefGoogle Scholar
  53. 53.
    Hakonarson H, Thorvaldsson S, Helgadottir A, et al.: Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. JAMA 2005, 293:2245–2256.PubMedCrossRefGoogle Scholar
  54. 54.
    Celik P, Sakar A, Havlucu Y, et al.: Short-term effects of montelukast in stable patients with moderate to severe COPD. Respir Med 2005, 99:444–450.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Asthma and Allergic Disease Center, Beirne Carter Center for Immunology ResearchUniversity of Virginia Health SystemCharlottesvilleUSA

Personalised recommendations