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Expanding roles for leukotrienes in airway inflammation

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Abstract

Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase pathway of arachidonic acid metabolism. Cysteinyl (cys) LTs C4, D4, and E4 are long known to contribute to airway contractile responses via ligation of the cysLT1 receptor, and cysLT1 antagonists are beneficial in some patients with asthma. Research advances over the past several years suggest that cysLT1 also mediates the ability of cysLTs to modulate inflammation, immune responses, and airway remodeling. Although less is known about an additional receptor, cysLT2, emerging evidence indicates that it likely also contributes to cysLT actions promoting inflammation, vascular permeability, and perhaps fibrosis. LTB4, best known as a neutrophil chemoattractant, is now recognized to exert other important effects contributing to inflammatory and immune responses. These recent data highlight a growing appreciation for LTs as pleiotropic effectors, which are integral components in the network of molecules that mediate the expression of asthma.

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References and Recommended Reading

  1. Peters-Golden M, Henderson W Jr: Leukotrienes. N Engl J Med 2007, 357:1841–1854.

    Article  PubMed  CAS  Google Scholar 

  2. Zhu J, Qiu YS, Figueroa DJ, et al.: Localization and upregulation of cysteinyl leukotriene-1 receptor in asthmatic bronchial mucosa. Am J Respir Cell Mol Biol 2005, 33:531–540.

    Article  PubMed  CAS  Google Scholar 

  3. Woszczek G, Chen LY, Nagineni S, et al.: Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor. J Allergy Clin Immunol 2008, 121:215–221.

    Article  PubMed  CAS  Google Scholar 

  4. Ichiyama T, Kajimoto M, Hasegawa M, et al.: Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. Clin Exp Allergy 2007, 37:608–614.

    Article  PubMed  CAS  Google Scholar 

  5. Jiang Y, Kanaoka Y, Feng C, et al.: Cutting edge: interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling. J Immunol 2006, 177:2755–2759.

    PubMed  CAS  Google Scholar 

  6. Wong WS, Zhu H, Liao W: Cysteinyl leukotriene receptor antagonist MK-571 alters bronchoalveolar lavage fluid proteome in a mouse asthma model. Eur J Pharmacol 2007, 575:134–141.

    Article  PubMed  CAS  Google Scholar 

  7. Kim DC, Hsu FI, Barrett NA, et al.: Cysteinyl leukotrienes regulate Th2 cell-dependent pulmonary inflammation. J Immunol 2006, 176:4440–4448.

    PubMed  CAS  Google Scholar 

  8. Stelmach I, Bobrowska-Korzeniowska M, Majak P, et al.: The effect of montelukast and different doses of budesonide on IgE serum levels and clinical parameters in children with newly diagnosed asthma. Pulm Pharmacol Ther 2005, 18:374–380.

    Article  PubMed  CAS  Google Scholar 

  9. Okunishi K, Dohi M, Nakagome K, et al.: A novel role of cysteinyl leukotrienes to promote dendritic cell activation in the antigen-induced immune responses in the lung. J Immunol 2004, 173:6393–6402.

    PubMed  CAS  Google Scholar 

  10. Thivierge M, Stankova J, Rola-Pleszczynski M: Toll-like receptor agonists differentially regulate cysteinyl-leukotriene receptor 1 expression and function in human dendritic cells. J Allergy Clin Immunol 2006, 117:1155–1162.

    Article  PubMed  CAS  Google Scholar 

  11. Robbiani D, Finch R, Jager D, et al.: The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3b, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 2000, 103:757–768.

    Article  PubMed  CAS  Google Scholar 

  12. Parameswaran K, Liang H, Fanat A, et al.: Role for cysteinyl leukotrienes in allergen-induced change in circulating dendritic cell number in asthma. J Allergy Clin Immunol 2004, 114:73–79.

    Article  PubMed  CAS  Google Scholar 

  13. Lamoureux J, Stankova J, Rola-Pleszczynski M: Leukotriene D4 enhances immunoglobulin production in CD40-activated human B lymphocytes. J Allergy Clin Immunol 2006, 117:924–930.

    Article  PubMed  CAS  Google Scholar 

  14. Spinozzi F, Russano AM, Piattoni S, et al.: Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes. Clin Exp Allergy 2004, 34:1876–1882.

    Article  PubMed  CAS  Google Scholar 

  15. Prinz I, Gregoire C, Mollenkopf H, et al.: The type 1 cysteinyl leukotriene receptor triggers calcium influx and chemotaxis in mouse alpha beta-and gamma delta effector T cells. J Immunol 2005, 175:713–719.

    PubMed  CAS  Google Scholar 

  16. Henderson W Jr, Tang L-O, Chu S-J, 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.

    PubMed  Google Scholar 

  17. Muz MH, Deveci F, Bulut Y, et al.: The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model. Exp Mol Med 2006, 38:109–118.

    PubMed  CAS  Google Scholar 

  18. Lee KS, Kim SR, Park HS, et al.: Cysteinyl leukotriene upregulates IL-11 expression in allergic airway disease of mice. J Allergy Clin Immunol 2007, 119:141–149.

    Article  PubMed  CAS  Google Scholar 

  19. Henderson WR Jr, Chiang GK, Tien YT, Chi EY: Reversal of allergen-induced airway remodeling by cysLT1 receptor blockade. Am J Respir Crit Care Med 2006, 173:718–728.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    PubMed  Google Scholar 

  21. Failla M, Genovese T, Mazzon E, et al.: Pharmacological inhibition of leukotrienes in an animal model of bleomycininduced acute lung injury. Respir Res 2006, 7:137.

    Article  PubMed  CAS  Google Scholar 

  22. Kelly MM, Chakir J, Vethanayagam D, et al.: Montelukast treatment attenuates the increase in myofibroblasts following low-dose allergen challenge. Chest 2006, 130:741–753.

    Article  PubMed  CAS  Google Scholar 

  23. Kato J, Kohyama T, Okazaki H, et al.: Leukotriene D4 potentiates fibronectin-induced migration of human lung fibroblasts. Clin Immunol 2005, 117:177–181.

    Article  PubMed  CAS  Google Scholar 

  24. Yoshisue H, Kirkham-Brown J, Healy E, et al.: Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts. J Allergy Clin Immunol 2007, 119:132–140.

    Article  PubMed  CAS  Google Scholar 

  25. Schmidt M, Sun G, Stacey MA, et al.: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003, 171:380–389.

    PubMed  CAS  Google Scholar 

  26. Vannella KM, McMillan TR, Charbeneau RP, et al.: Cysteinyl leukotrienes are autocrine and paracrine regulators of fibrocyte function. J Immunol 2007, 179:7883–7890.

    PubMed  CAS  Google Scholar 

  27. Figueroa DJ, Borish L, Baramki D, et al.: Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin Exp Allergy 2003, 33:1380–1388.

    Article  PubMed  CAS  Google Scholar 

  28. Mita H, Hasegawa M, Saito H, Akiyama K: 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.

    Article  PubMed  CAS  Google Scholar 

  29. Corrigan C, Mallett K, Ying S, et al.: Expression of the cysteinyl leukotriene receptors cysLT1 and cysLT2 in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis. J Allergy Clin Immunol 2005, 115:316–322.

    Article  PubMed  CAS  Google Scholar 

  30. Fujii M, Tanaka H, Abe S: Interferon-gamma up-regulates expression of cysteinyl leukotriene type 2 receptors on eosinophils in asthmatic patients. Chest 2005, 128:3148–3155.

    Article  PubMed  CAS  Google Scholar 

  31. 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, 100:11589–11593.

    Article  PubMed  CAS  Google Scholar 

  32. Early SB, Barekzi E, Negri J, et al.: Concordant modulation of cysteinyl leukotriene receptor expression by IL-4 and IFN-gamma on peripheral immune cells. Am J Respir Cell Mol Biol 2007, 36:715–720.

    Article  PubMed  CAS  Google Scholar 

  33. Beller TC, Maekawa A, Friend DS, et al.: Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J Biol Chem 2004, 279:46129–46134.

    Article  PubMed  CAS  Google Scholar 

  34. Uzonyi B, Lotzer K, Jahn S, et al.: Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. Proc Natl Acad Sci U S A 2006, 103:6326–6331.

    Article  PubMed  CAS  Google Scholar 

  35. Thompson C, Cloutier A, Bosse Y, et al.: Signaling by the cysteinyl-leukotriene receptor 2: involvement in chemokine gene transcription. J Biol Chem 2008, 283:1974–1984.

    Article  PubMed  CAS  Google Scholar 

  36. Pillai SG, Cousens DJ, Barnes AA, et al.: A coding polymorphism in the cysLT2 receptor with reduced affinity to LTD4 is associated with asthma. Pharmacogenetics 2004, 14:627–633.

    Article  PubMed  CAS  Google Scholar 

  37. Jiang Y, Borrelli LA, Kanaoka Y, et al.: CysLT2 receptors interact with cysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells. Blood 2007, 110:3263–3270.

    Article  PubMed  CAS  Google Scholar 

  38. Klotsman M, York TP, Pillai SG, et al.: Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast. Pharmacogenet Genomics 2007, 17:189–196.

    Article  PubMed  CAS  Google Scholar 

  39. 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, 25:4615–4627.

    Article  PubMed  CAS  Google Scholar 

  40. Wenzel SE, Szefler SJ, Leung DY, et al.: Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997, 156:737–743.

    PubMed  CAS  Google Scholar 

  41. Kostikas K, Gaga M, Papatheodorou G, et al.: Leukotriene B4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma. Chest 2005, 127:1553–1559.

    Article  PubMed  CAS  Google Scholar 

  42. Tager AM, Bromley SK, Medoff BD, et al.: Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 2003, 4:982–990.

    Article  PubMed  CAS  Google Scholar 

  43. Miyahara N, Swanson BJ, Takeda K, et al.: Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004, 10:865–869.

    Article  PubMed  CAS  Google Scholar 

  44. Miyahara N, Takeda K, Miyahara S, et al.: Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness. Am J Respir Crit Care Med 2005, 172:161–167.

    Article  PubMed  Google Scholar 

  45. Terawaki K, Yokomizo T, Nagase T, et al.: Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses. J Immunol 2005, 175:4217–4225.

    PubMed  CAS  Google Scholar 

  46. Islam SA, Thomas SY, Hess C, et al.: The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans. Blood 2006, 107:444–453.

    Article  PubMed  CAS  Google Scholar 

  47. Weller CL, Collington SJ, Brown JK, et al.: Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. J Exp Med 2005, 201:1961–1971.

    Article  PubMed  CAS  Google Scholar 

  48. Iikura M, Suzukawa M, Yamaguchi M, et al.: 5-Lipoxygenase products regulate basophil functions: 5-oxo-ETE elicits migration, and leukotriene B4 induces degranulation. J Allergy Clin Immunol 2005, 116:578–585.

    Article  PubMed  CAS  Google Scholar 

  49. Heller EA, Liu E, Tager AM, et al.: Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation 2005, 112:578–586.

    Article  PubMed  Google Scholar 

  50. Chupp GL, Lee CG, Jarjour N, et al.: A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 2007, 357:2016–2027.

    Article  PubMed  CAS  Google Scholar 

  51. Reese TA, Liang HE, Tager AM, et al.: Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 2007, 447:92–96.

    Article  PubMed  CAS  Google Scholar 

  52. Peters-Golden M: Do anti-leukotriene agents inhibit asthmatic inflammation? Clin Exp Allergy 2003, 33:721–724.

    Article  PubMed  CAS  Google Scholar 

  53. Peters-Golden M, Henderson WR Jr: The role of leukotrienes in allergic rhinitis. Ann Allergy Asthma Immunol 2005, 94:609–618; quiz 618–620, 669.

    Article  PubMed  CAS  Google Scholar 

  54. Wenzel SE, Trudeau JB, Kaminsky DA, et al.: Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma. Am J Respir Crit Care Med 1995, 152:897–905.

    PubMed  CAS  Google Scholar 

  55. 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.

    Article  PubMed  CAS  Google Scholar 

  56. Kane G, Pollice M, Kim C, et al.: A controlled trial of the effect of the 5-lipoxygenase inhibitor, zileuton, on lung inflammation produced by segmental antigen challenge in human beings. J Allergy Clin Immunol 1996, 97:646–654.

    Article  PubMed  CAS  Google Scholar 

  57. Sandrini A, Ferreira IM, Gutierrez C, et al.: Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma. Chest 2003, 124:1334–1340.

    Article  PubMed  CAS  Google Scholar 

  58. Bisgaard H, Loland L, Anhoj J: NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 1999, 160:1227–1231.

    PubMed  CAS  Google Scholar 

  59. Montuschi P, Mondino C, Koch P, et al.: Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma. Chest 2007, 132:1876–1881.

    Article  PubMed  CAS  Google Scholar 

  60. Larsson BM, Kumlin M, Sundblad BM, et al.: Effects of 5-lipoxygenase inhibitor zileuton on airway responses to inhaled swine house dust in healthy subjects. Respir Med 2006, 100:226–237.

    Article  PubMed  Google Scholar 

  61. Jayaram L, Duong M, Pizzichini MM, et al.: Failure of montelukast to reduce sputum eosinophilia in high-dose corticosteroid-dependent asthma. Eur Respir J 2005, 25:41–46.

    Article  PubMed  CAS  Google Scholar 

  62. Hasday J, Meltzer S, Moore W, et al.: Anti-inflammatory effects of zileuton in a subpopulation of allergic asthmatics. Am J Respir Crit Care Med 2000, 161:1229–1236.

    PubMed  CAS  Google Scholar 

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  1. Division of Pulmonary and Critical Care Medicine, 6301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5642, USA

    Marc Peters-Golden

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Peters-Golden, M. Expanding roles for leukotrienes in airway inflammation. Curr Allergy Asthma Rep 8, 367–373 (2008). https://doi.org/10.1007/s11882-008-0057-z

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