Current Infectious Disease Reports

, Volume 14, Issue 2, pp 147–154 | Cite as

Leukotriene Inhibitors in Sinusitis

Upper Respiratory, Head, and Neck Infections (I Brook, Section Editor)

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 including chronic sinusitis, particularly those sub-types involving eosinophils. Leukotrienes can be separated into the fairly well characterized cysteinyl leukotrienes and 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 and as such, two approaches have been developed that led to drugs approved for treatment of 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 will focus on the role that leukotrienes play in chronic sinusitis and consider the rationale for choosing either a leukotriene antagonist or synthesis inhibitor as a treatment option. We will also discuss off-label uses for other medications that might be useful in these diseases as they relate to their ability to modulate leukotriene action.

Keywords

Sinusitis Leukotriene Inhibitor Arachidonic acid Receptor 

Notes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology. Otolaryngol Head Neck Surg. 2003;129:S1–S32.PubMedCrossRefGoogle Scholar
  2. 2.
    Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing definitions for clincal research and patient care. J Allergy Clin Immunol. 2004;114:S155–212.CrossRefGoogle Scholar
  3. 3.
    Slavin RG, Spector SL, Berstein IL, et al. The diagnosis and management of sinusitis: a practice parameter update. J Allergy Clin Immunol. 2005;116:S13–47.PubMedCrossRefGoogle Scholar
  4. 4.
    •• Payne SC, Borish L, Steinke JW. Genetics and phenotyping in chronic sinusitis. J Allergy Clin Immunol. 2011;in press. Rather than lumping all forms of sinusitis together, this paper discusses the various subtypes of sinusitis and different approaches to treatment. Google Scholar
  5. 5.
    Yopp AC, Randolph GJ, Bromberg JS. Leukotrienes, sphingolipids, and leukocyte trafficking. J Immuol. 2003;171:5–10.Google Scholar
  6. 6.
    Peters-Golden M, Brock TG. Intracellular compartmentalization of leukotriene synthesis: unexpected nuclear secrets. FEBS Lett. 2001;487:323–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Ferguson AD, McKeever BM, Xu S, et al. Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science. 2007;317:510–2.PubMedCrossRefGoogle Scholar
  8. 8.
    Ago H, Kanaoka Y, Irikura D, et al. Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis. Nature. 2007;448:609–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Christmas P, Weber BM, McKee M, et al. Membrane localization and topology of leukotriene C4 synthase. J Biol Chem. 2002;277:28902–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999;399:789–93.PubMedCrossRefGoogle Scholar
  11. 11.
    Heise CE, O’Dowd BF, Figueroa DJ, et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem. 2000;275:30531–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Walch L, Norel X, Back M, et al. Pharmacological evidence for a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle. Br J Pharmacol. 2002;137:1339–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Nonaka Y, Hiramoto T, Fujita N. Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods. Biochem Biophys Res Commun. 2005;337:281–8.PubMedCrossRefGoogle Scholar
  14. 14.
    •• Paruchuri S, Tashimo H, Feng C, et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med. 2009;206:2543–2555. This is one of the first papers that describes a receptor for LTE 4 , providing functional evidence in support of previous pharmacological data. PubMedCrossRefGoogle Scholar
  15. 15.
    • Maekawa A, Kanaoka Y, Xing W, et al. Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors. Proc Natl Acad Sci U S A. 2008;105:16695–16700. Using knock-out mice this papers demonstrates that a receptor for LTE 4 exists based on responsiveness to LTE 4 in the absence of other known CysLT receptors. PubMedCrossRefGoogle Scholar
  16. 16.
    Ciana P, Fumagalli M, Trincavelli ML, et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J. 2006;25:4615–27.PubMedCrossRefGoogle Scholar
  17. 17.
    Maekawa A, Balestrieri B, Austen KF, et al. GPR17 is a negative regulator of the cysteinyl leukotriene 1 receptor response to leukotriene D4. Proc Natl Acad Sci U S A. 2009;106:11685–90.PubMedCrossRefGoogle Scholar
  18. 18.
    Wunder F, Tinel H, Kast R, et al. Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT(2)) receptor. Br J Pharmacol. 160:399–409.Google Scholar
  19. 19.
    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;163:226–33.Google Scholar
  20. 20.
    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;33:1380–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Sousa AR, Parikh A, Scadding G, et al. Leukotriene-receptor expression on nasal mucosal inflammatory cells in asprin-sensitive rhinosinusitis. N Engl J Med. 2002;347:1493–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Sjostrom M, Johansson AS, Schroder O, et al. Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endotheilial cells. Arterioscler Thromb Vasc Biol. 2003;23:E37–41.PubMedCrossRefGoogle Scholar
  23. 23.
    Yoshisue H, Kirkham-Brown J, Healy E, et al. Cysteinyl leukotrienes synergize with growth factors too induce proliferation of human bronchial fibroblasts. J Allergy Clin Immunol. 2007;119:132–40.PubMedCrossRefGoogle Scholar
  24. 24.
    Steinke JW, Crouse CD, Bradley D, et al. Characterization of interleukin-4 stimulated nasal polyp fibroblasts. Am J Respir Cell Mol Biol. 2004;30:212–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Tager AM, Luster AD. BLT1 and BLT2: the leukotriene B(4) receptors. Prost Leukot Essent Fatty Acids. 2003;69:123–34.CrossRefGoogle Scholar
  26. 26.
    Yokomizo T, Izumi T, Shimizu T. Co-expression of two LTB4 receptors in human mononuclear cells. Life Sci. 2001;68:2207–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Mellor EA, Austen KF, Boyce JA. Cysteinyl leukotrienes and uridine diphosphate induce cytokine generation by human mast cells through an interleukin 4-regulated pathway that is inhibited by leukotriene receptor antagonists. J Exp Med. 2002;195:583–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Mellor EA, Frank N, Soler D, et al. Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R. Proc Natl Acad Sci U S A. 2003;100:11589–93.PubMedCrossRefGoogle Scholar
  29. 29.
    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;167:2855–60.PubMedGoogle Scholar
  30. 30.
    Early SB, Barekzi E, Negri J, et al. Concordant modulation of cysteinyl leukotriene receptor expression by IL-4 and IFN-γ on peripheral immune cells. Am J Respir Cell Mol Biol. 2007;36:715–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Fujii M, Tanaka H, Abe S. Interferon-gamma up-regulates expression of cysteinyl leukotriene type 2 receptors on eosinophils in asthmatic patients. Chest. 2005;128:3148–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Lotzer K, Spanbroek R, Hildner M, et al. Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler Thromb Vasc Biol. 2003;23:e32–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Woszczek G, Chen LY, Nagineni S, et al. IFN-gamma induces cysteinyl leukotriene receptor 2 expression and enhances the responsiveness of human endothelial cells to cysteinyl leukotrienes. J Immunol. 2007;178:5262–70.PubMedGoogle Scholar
  34. 34.
    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;165:5221–6.PubMedGoogle Scholar
  35. 35.
    Qiu 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;103:6913–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Samter M, Beers Jr RF. Intolerance to aspirin. Clinical studies and consideration of its pathogenesis. Ann Intern Med. 1968;68:975–83.PubMedGoogle Scholar
  37. 37.
    Szczeklik A, Nizankowska E. Clinical features and diagnosis of aspirin induced asthma. Thorax. 2000;55:S42–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Steinke JW, Bradley D, Arango P, et al. Cytseinyl leukotriene expression in chronic hyperplastic sinusitis-nasal polyposis: importance to eosinophilia and asthma. J Allergy Clin Immunol. 2003;111:342–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Perez-Novo CA, Watelet JB, Claeys C, et al. Prostaglandin, leukotiene, and lipoxin balance in chronic rhinosinusitis with and without nasal polyposis. J Allergy Clin Immunol. 2005;115:1189–96.PubMedCrossRefGoogle Scholar
  40. 40.
    Cowburn AS, Sladek K, Soja J, et al. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998;101:834–46.PubMedCrossRefGoogle Scholar
  41. 41.
    Adamjee J, Suh YJ, Park HS, et al. Expression of 5-lipoxygenase and cyclooxygenase pathway enzymes in nasal polyps of patients with aspirin-intolerant asthma. J Pathol. 2006;209:392–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis. 1991;143:1025–9.PubMedGoogle Scholar
  43. 43.
    Corrigan C, Mallett K, Ying S, et al. Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis. J Allergy Clin Immunol. 2005;115:316–22.PubMedCrossRefGoogle Scholar
  44. 44.
    Bachert C, Wagenmann M, Hauser U, et al. IL-5 synthesis is upregulated in human nasal polyp tissue. J Allergy Clin Immunol. 1997;99:837–42.PubMedCrossRefGoogle Scholar
  45. 45.
    Bachert C, Gevaert P, van Cauwenberge P. Nasal polyposis- a new concept on the formation of polyps. ACI International. 1999;11:130–5.Google Scholar
  46. 46.
    Elovic A, Wong DT, Weller PF, et al. Expression of transforming growth factors-alpha and beta 1 messenger RNA and product by eosinophils in nasal polyps. J Allergy Clin Immunol. 1994;93:864–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy. 2006;61:1280–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Minshall EM, Cameron L, Lavigne F, et al. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Amer J Resp Cell Mol Biol. 1997;17:683–90.Google Scholar
  49. 49.
    Hamilos DL, Leung DYM, Huston DP, et al. GM-CSF, IL-5, and RANTES immunoreactivity and mRNA expression in chronic hyperplastic sinusitis with nasal polyposis. Clin Exp Allergy. 1998;28:1145–52.PubMedCrossRefGoogle Scholar
  50. 50.
    Israel E, Fischer AR, Rosenberg MA, et al. The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. Amer Rev Respir Dis. 1993;148:1447–51.CrossRefGoogle Scholar
  51. 51.
    Sladek K, Szczeklik A. Cysteinyl leukotrienes overproduction and mast cell activation in aspirn-provoked bronchospasm in asthma. Eur Respir J. 1993;6:391–9.PubMedGoogle Scholar
  52. 52.
    Daffern PJ, Muilenburg D, Hugli TE, et al. Association of urinary leukotriene E4 excretion during aspirin challenges with severity of resiratory responses. J Allergy Clin Immunol. 1999;104:559–64.PubMedCrossRefGoogle Scholar
  53. 53.
    Arm JP, O’Hickey S, Spur BW, et al. Airway responsiveness to histamine and leukotriene E4 in subjects with aspirin-induced asthma. Am Rev Respir Dis. 1989;140:148–53.PubMedCrossRefGoogle Scholar
  54. 54.
    Ding XZ, Talamonti MS, Bell Jr RH, et al. A novel anti-pancreatic cancer agent, LY293111. Anti Canc Drugs. 2005;16:467–73.CrossRefGoogle Scholar
  55. 55.
    Dahlen B, Nizankowska E, Szczeklik A. Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Critc Care Med. 1998;157:1187–94.Google Scholar
  56. 56.
    Kieff DA, Busaba NY. Efficacy of montelukast in the treatment of nasal polyposis. Ann Otol Rhinol Laryngol. 2005;114:941–5.PubMedGoogle Scholar
  57. 57.
    • Schaper C, Noga O, Koch B, et al. Anti-inflammatory properties of montelukast, a leukotriene receptor antagonist in patients with asthma and nasal polyposis. J Investig Allergol Clin Immunol. 2011;21:51–58. Monteluekast was shown to mediate slight improvements in chronic sinusitis symptoms and reduction in nasal polyps. PubMedGoogle Scholar
  58. 58.
    Wilson AM, White PS, Gardiner Q, et al. Effects of leukotriene receptor antagonist therapy in patients with chronic rhinosinusitis in a real life rhinology clinic setting. Rhinology. 2001;39:142–6.PubMedGoogle Scholar
  59. 59.
    Parnes SM, Churna AV. Acute effects of antileukotrienes on sinonasal polyposis and sinusitis. ENT Journal. 2000;79:18–21.Google Scholar
  60. 60.
    Parnes SM. The role of leukotriene inhibitors in patients with paranasal sinus disease. Curr Opin Otolaryngol Head Neck Surg. 2003;11:184–91.PubMedCrossRefGoogle Scholar
  61. 61.
    Di Rienzo L, Artuso A, Cerqua N. Antileukotrienes in the prevention of postoperative recurrence of nasal polyposis in ASA syndrome. Acta Otorhinolaryngol Ital. 2000;20:336–42.PubMedGoogle Scholar
  62. 62.
    Grundmann T, Topfner M. Treatment of ASS-Associated Polyposis (ASSAP) with a cysteinyl leukotriene receptor antagonist - a prospective drug study on its antiinflammatory effects. Laryngorhinootologie. 2001;80:576–82.PubMedCrossRefGoogle Scholar
  63. 63.
    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 C4 synthase expression by interleukin 4. J Exp Med. 2001;193:123–33.PubMedCrossRefGoogle Scholar
  64. 64.
    Mellor EA, Maekawa A, Austen KF, et al. Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci USA. 2001;98:7964–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Lin DA, Boyce JA. IL-4 regulates MEK expression required for lysophosphatidic acid-mediated chemokine generation by human mast cells. J Immunol. 2005;175:5430–8.PubMedGoogle Scholar
  66. 66.
    Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133–41.PubMedCrossRefGoogle Scholar
  67. 67.
    •• Kim S, Marigowda G, Oren E, et al. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010;125:1336–1343. Anti-IL-5 treatment reduces eosinophil number and therefore leukotriene levels in sinus tissue. An additional benefit would be the reduction of steroid levels required in the treatment of chronic sinusitis and associated nasal polyposis. PubMedCrossRefGoogle Scholar
  68. 68.
    Bain BJ. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. Am J Hematol. 2004;77:82–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Koury MJ, Newman JH, Murray JJ. Reversal of hypereosinophilic syndrome and lymphomatoid papulosis with mepolizumab and imatinib. Am J Med. 2003;115:587–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Amrol D, Murray JJ. Alternative medical treatment strategies for chronic hyperplastic eosinophilic sinusitis. Curr Opin Otolaryngol Head Neck Surg. 2005;13:55–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Wallwork B, Coman W, Mackay-Sim A, et al. Effect of clarithromycin on nuclear factor-kappa B and transforming growth factor-beta in chronic rhinosinusitis. Laryngoscope. 2004;114:286–90.PubMedCrossRefGoogle Scholar
  72. 72.
    Katsuta S, Osafune H, Takita R, et al. Therapeutic effect of roxithromycin on chronic sinusitis with nasal – polyps clinical, computed tomography, and electron microscopy analysis. Nihon Jibiinkoka Gakkai Kaiho. 2002;105:1189–97.PubMedCrossRefGoogle Scholar
  73. 73.
    Bradley JD, Dmitrienko AA, Kivitz AJ, et al. A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis. J Rheumatol. 2005;32:417–23.PubMedGoogle Scholar
  74. 74.
    Miyake A, Yamamoto H, Takebayashi Y, et al. The novel natural product YM-26567-1 [(+)-trans-4-(3-dodecanoyl-2,4,6- trihydroxyphenyl)-7-hydroxy-2-(4-hydroxyphenyl)chroman]: a competitive inhibitor of group II phospholipase A2. J Pharmacol Exp Ther. 1992;263:1302–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Asthma and Allergic Diseases CenterUniversity of Virginia Health SystemCharlottesvilleUSA
  2. 2.Carter Center for Immunology ResearchUniversity of Virginia Health SystemCharlottesvilleUSA

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