The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders
Abstract
1. Introduction
2. Biosynthesis and Metabolism of LTs
3. Expression of LT Receptors and Their Associated Signaling Pathways
3.1. LTB4 Receptors: BLT1 and BLT2
3.2. CysLTs Receptors: CysLT1 and CysLT2
3.3. GPR99
4. LTs and Allergic Diseases
4.1. Asthma
4.1.1. Pathology
4.1.2. The LTB4–BLT1 Pathway in Asthma
4.1.3. The CysLT Pathway in Asthma
4.2. Exercise-Induced Asthma (EIA)
4.3. Aspirin-Sensitive Asthma (ASA)
4.4. Allergic Rhinitis (AR)
4.5. Atopic Dermatitis (AD)
4.6. Allergic Conjunctivitis
4.7. Anaphylaxis
5. Urinary LTE4 as a Biomarker of Allergic Disease
6. Other Diseases
7. Conclusions
Conflicts of Interest
Abbreviations
PG | prostaglandin |
LT | leukotriene |
AA | arachidonic acid |
GPCR | G-protein-coupled receptor |
LTB4 | leukotriene B4 |
PLA2 | phospholipase A2 |
5-LO | 5-lipoxygenase |
COX | cyclooxygenase |
5-HpETE | 5-hydroxyperoxyeicosatetraenoic acid |
LTA4 | leukotriene A4 |
LTA4H | leukotriene A4 hydrolase |
LTC4S | leukotriene C4 synthase |
COPD | chronic obstructive pulmonary disease |
AMD | age-related macular degeneration |
BLT1 | LTB4 receptor 1 |
BLT2 | LTB4 receptor 2 |
12-HHT | 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid |
OXGR1 | oxoglutarate receptor |
ICS | inhaled corticosteroid |
AHR | hyper-responsiveness |
BAL | bronchoalveolar lavage |
EIA | Exercise-induced asthma |
LTRA | leukotriene receptor antagonist |
FLAP | five-lipoxygenase-activating protein |
EBC | exhaled breath condensate |
ASA | aspirin-sensitive asthma |
AERD | aspirin-exacerbated respiratory disease |
IL | interleukin |
AR | allergic rhinitis |
SAH | H1-antihistamines |
AD | atopic dermatitis |
MC | mast cell |
MCAS | mast cell activation syndrome |
SM | systemic mastocytosis |
uLTE4 | urinary LTE4 |
References
- Shimizu, T. Lipid mediators in health and disease: Enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 2009, 49, 123–150. [Google Scholar] [CrossRef] [PubMed]
- Radmark, O.; Werz, O. 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim. Biophys. Acta 2015, 1851, 331–339. [Google Scholar] [CrossRef] [PubMed]
- Back, M.; Powell, W.S. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. Br. J. Pharmacol. 2014, 171, 3551–3574. [Google Scholar] [CrossRef] [PubMed]
- Liu, M.; Yokomizo, T. The role of leukotrienes in allergic diseases. Allergol. Int. 2015, 64, 17–26. [Google Scholar] [CrossRef] [PubMed]
- Haeggstrom, J.Z.; Funk, C.D. Lipoxygenase and leukotriene pathways: Biochemistry, biology, and roles in disease. Chem. Rev. 2011, 111, 5866–5898. [Google Scholar] [CrossRef] [PubMed]
- White, A.A.; Stevenson, D.D. Aspirin-Exacerbated Respiratory Disease. N. Engl. J. Med. 2018, 379, 1060–1070. [Google Scholar] [CrossRef]
- Cuzzo, B.; Lappin, S.L. Physiology, Leukotrienes; StatPearls: Treasure Island, FL, USA, 2019. [Google Scholar]
- Satpathy, S.R.; Jala, V.R. Crystalline silica-induced leukotriene B4-dependent inflammation promotes lung tumour growth. Nat. Commun. 2015, 6, 7064. [Google Scholar] [CrossRef]
- Jala, V.R.; Bodduluri, S.R. The yin and yang of leukotriene B4 mediated inflammation in cancer. Semin. Immunol. 2017, 33, 58–64. [Google Scholar] [CrossRef]
- Park, J.; Jang, J.H. BLT2, a leukotriene B4 receptor 2, as a novel prognostic biomarker of triple-negative breast cancer. BMB Rep. 2018, 51, 373–377. [Google Scholar] [CrossRef]
- Houthuijzen, J.M.; Daenen, L.G. Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response. Nat. Commun. 2014, 5, 5275. [Google Scholar] [CrossRef]
- Mathis, S.P.; Jala, V.R. Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis. J. Immunol. 2010, 185, 3049–3056. [Google Scholar] [CrossRef] [PubMed]
- Iizuka, Y.; Okuno, T. Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis. FASEB J. 2010, 24, 4678–4690. [Google Scholar] [CrossRef] [PubMed]
- Paruchuri, S.; Tashimo, H. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J. Exp. Med. 2009, 206, 2543–2555. [Google Scholar] [CrossRef] [PubMed]
- Foster, H.R.; Fuerst, E. Characterisation of P2Y(12) receptor responsiveness to cysteinyl leukotrienes. PLoS ONE 2013, 8, e58305. [Google Scholar] [CrossRef] [PubMed]
- Bankova, L.G.; Lai, J. Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99. Proc. Natl. Acad. Sci. USA 2016, 113, 6242–6247. [Google Scholar] [CrossRef] [PubMed]
- Ciana, P.; Fumagalli, M. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J. 2006, 25, 4615–4627. [Google Scholar] [CrossRef]
- Davenport, A.P.; Alexander, S.P. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: Recommendations for new pairings with cognate ligands. Pharmacol. Rev. 2013, 65, 967–986. [Google Scholar] [CrossRef]
- Krishnamoorthy, S.; Recchiuti, A. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc. Natl. Acad. Sci. USA 2010, 107, 1660–1665. [Google Scholar] [CrossRef]
- Chiang, N.; Fredman, G. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 2012, 484, 524–528. [Google Scholar] [CrossRef]
- Dalli, J.; Winkler, J.W. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 2013, 20, 188–201. [Google Scholar] [CrossRef]
- Wittamer, V.; Gregoire, F. The C-terminal nonapeptide of mature chemerin activates the chemerin receptor with low nanomolar potency. J. Biol. Chem. 2004, 279, 9956–9962. [Google Scholar] [CrossRef] [PubMed]
- Wittamer, V.; Franssen, J.D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 2003, 198, 977–985. [Google Scholar] [CrossRef] [PubMed]
- Arita, M.; Bianchini, F. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 2005, 201, 713–722. [Google Scholar] [CrossRef] [PubMed]
- Yokomizo, T. Two distinct leukotriene B4 receptors, BLT1 and BLT2. J. BioChem. 2015, 157, 65–71. [Google Scholar] [CrossRef] [PubMed]
- Yokomizo, T.; Izumi, T. A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997, 387, 620–624. [Google Scholar] [CrossRef]
- Qiu, H.; Johansson, A.S. Differential induction of BLT receptor expression on human endothelial cells by lipopolysaccharide, cytokines, and leukotriene B4. Proc. Natl. Acad. Sci. USA 2006, 103, 6913–6918. [Google Scholar] [CrossRef] [PubMed]
- Wada, K.; Arita, M. Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation. FASEB J. 2006, 20, 1785–1792. [Google Scholar] [CrossRef]
- Sun, R.; Ba, X. Leukotriene B4 regulates proliferation and differentiation of cultured rat myoblasts via the BLT1 pathway. Mol. Cells 2009, 27, 403–408. [Google Scholar] [CrossRef]
- Yokomizo, T.; Kato, K. A second leukotriene B(4) receptor, BLT2. A new therapeutic target in inflammation and immunological disorders. J. Exp. Med. 2000, 192, 421–432. [Google Scholar] [CrossRef]
- Yokomizo, T.; Ogawa, Y. cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase. J. Biol. Chem. 1996, 271, 2844–2850. [Google Scholar] [CrossRef]
- Okuno, T.; Iizuka, Y. 12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2. J. Exp. Med. 2008, 205, 759–766. [Google Scholar] [CrossRef] [PubMed]
- Liu, M.; Saeki, K. 12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor. J. Exp. Med. 2014, 211, 1063–1078. [Google Scholar] [CrossRef] [PubMed]
- Iwamoto, S.; Koga, T. Non-steroidal anti-inflammatory drug delays corneal wound healing by reducing production of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2. Sci. Rep. 2017, 7, 13267. [Google Scholar] [CrossRef] [PubMed]
- Shigematsu, M.; Koga, T. Leukotriene B4 receptor type 2 protects against pneumolysin-dependent acute lung injury. Sci. Rep. 2016, 6, 34560. [Google Scholar] [CrossRef] [PubMed]
- Saeki, K.; Yokomizo, T. Identification, signaling, and functions of LTB4 receptors. Semin. Immunol. 2017, 33, 30–36. [Google Scholar] [CrossRef] [PubMed]
- Thompson-Souza, G.A.; Gropillo, I. Cysteinyl Leukotrienes in Eosinophil Biology: Functional Roles and Therapeutic Perspectives in Eosinophilic Disorders. Front. Med. (Lausanne) 2017, 4, 106. [Google Scholar] [CrossRef]
- Wunder, F.; Tinel, H. Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (CysLT(2)) receptor. Br. J. Pharmacol. 2010, 160, 399–409. [Google Scholar] [CrossRef] [PubMed]
- Lynch, K.R.; O’Neill, G.P. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999, 399, 789–793. [Google Scholar] [CrossRef]
- Heise, C.E.; O’Dowd, B.F. Characterization of the human cysteinyl leukotriene 2 receptor. J. Biol. Chem. 2000, 275, 30531–30536. [Google Scholar] [CrossRef]
- Mechiche, H.; Naline, E. Effects of cysteinyl leukotrienes in small human bronchus and antagonist activity of montelukast and its metabolites. Clin. Exp. Allergy 2003, 33, 887–894. [Google Scholar] [CrossRef]
- Figueroa, D.J.; Breyer, R.M. Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am. J. Respir. Crit. Care Med. 2001, 163, 226–233. [Google Scholar] [CrossRef] [PubMed]
- Hui, Y.; Cheng, Y. Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation 2004, 110, 3360–3366. [Google Scholar] [CrossRef] [PubMed]
- Maekawa, A.; Kanaoka, Y. Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors. Proc. Natl. Acad. Sci. USA 2008, 105, 16695–16700. [Google Scholar] [CrossRef] [PubMed]
- Kanaoka, Y.; Maekawa, A. Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand. J. Biol. Chem. 2013, 288, 10967–10972. [Google Scholar] [CrossRef] [PubMed]
- Shirasaki, H.; Kanaizumi, E. Expression and localization of GPR99 in human nasal mucosa. Auris Nasus Larynx 2017, 44, 162–167. [Google Scholar] [CrossRef] [PubMed]
- Hoffman, B.C.; Rabinovitch, N. Urinary Leukotriene E4 as a Biomarker of Exposure, Susceptibility, and Risk in Asthma: An Update. Immunol. Allergy Clin. N. Am. 2018, 38, 599–610. [Google Scholar] [CrossRef] [PubMed]
- Peebles, R.S., Jr.; Aronica, M.A. Proinflammatory Pathways in the Pathogenesis of Asthma. Clin. Chest Med. 2019, 40, 29–50. [Google Scholar] [CrossRef] [PubMed]
- Gelfand, E.W. Importance of the leukotriene B4-BLT1 and LTB4-BLT2 pathways in asthma. Semin. Immunol. 2017, 33, 44–51. [Google Scholar] [CrossRef]
- Miligkos, M.; Bannuru, R.R. Leukotriene-receptor antagonists versus placebo in the treatment of asthma in adults and adolescents: A systematic review and meta-analysis. Ann. Intern. Med. 2015, 163, 756–767. [Google Scholar] [CrossRef]
- Bruno, F.; Spaziano, G. Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma. Eur. J. Med. Chem. 2018, 153, 65–72. [Google Scholar] [CrossRef]
- Matsunaga, Y.; Fukuyama, S. Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia. FASEB J. 2013, 27, 3306–3314. [Google Scholar] [CrossRef] [PubMed]
- Kandhare, A.D.; Liu, Z. Therapeutic Potential of Morin in Ovalbumin-induced Allergic Asthma Via Modulation of SUMF2/IL-13 and BLT2/NF-kB Signaling Pathway. Curr. Mol. Pharmacol. 2019, 12, 122–138. [Google Scholar] [CrossRef] [PubMed]
- Liu, M.; Shen, J. Leukotriene B4 receptor 2 regulates the proliferation, migration, and barrier integrity of bronchial epithelial cells. J. Cell. Physiol. 2018, 233, 6117–6124. [Google Scholar] [CrossRef] [PubMed]
- Seymour, M.L.; Rak, S. Leukotriene and prostanoid pathway enzymes in bronchial biopsies of seasonal allergic asthmatics. Am. J. Respir. Crit. Care Med. 2001, 164, 2051–2056. [Google Scholar] [CrossRef] [PubMed]
- Zaitsu, M.; Hamasaki, Y. Leukotriene synthesis is increased by transcriptional up-regulation of 5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene C4 synthase in asthmatic children. J. Asthma 2003, 40, 147–154. [Google Scholar] [CrossRef] [PubMed]
- Pal, K.; Feng, X. Leukotriene A4 Hydrolase Activation and Leukotriene B4 Production by Eosinophils in Severe Asthma. Am. J. Respir. Cell Mol. Biol. 2019, 60, 413–419. [Google Scholar] [CrossRef] [PubMed]
- Kazani, S.; Planaguma, A. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J. Allergy Clin. Immunol. 2013, 132, 547–553. [Google Scholar] [CrossRef]
- Trischler, J.; Muller, C.M. Elevated exhaled leukotriene B(4) in the small airway compartment in children with asthma. Ann. Allergy Asthma Immunol. 2015, 114, 111–116. [Google Scholar] [CrossRef]
- Ohnishi, H.; Miyahara, N. The role of leukotriene B(4) in allergic diseases. Allergol. Int. 2008, 57, 291–298. [Google Scholar] [CrossRef]
- Loutsios, C.; Farahi, N. Biomarkers of eosinophilic inflammation in asthma. Expert Rev. Respir. Med. 2014, 8, 143–150. [Google Scholar] [CrossRef]
- Ito, K.; Herbert, C. Steroid-resistant neutrophilic inflammation in a mouse model of an acute exacerbation of asthma. Am. J. Respir. Cell Mol. Biol. 2008, 39, 543–550. [Google Scholar] [CrossRef] [PubMed]
- Wang, F.; He, X.Y. Different inflammatory phenotypes in adults and children with acute asthma. Eur. Respir. J. 2011, 38, 567–574. [Google Scholar] [CrossRef] [PubMed]
- Panettieri, R.A., Jr. Neutrophilic and Pauci-immune Phenotypes in Severe Asthma. Immunol. Allergy Clin. N. Am. 2016, 36, 569–579. [Google Scholar] [CrossRef] [PubMed]
- Chang, H.S.; Lee, T.H. Neutrophilic inflammation in asthma: Mechanisms and therapeutic considerations. Expert Rev. Respir. Med. 2017, 11, 29–40. [Google Scholar] [CrossRef] [PubMed]
- Ray, A.; Kolls, J.K. Neutrophilic Inflammation in Asthma and Association with Disease Severity. Trends Immunol. 2017, 38, 942–954. [Google Scholar] [CrossRef]
- Moore, W.C.; Hastie, A.T. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J. Allergy Clin. Immunol. 2014, 133, 1557–1563.e5. [Google Scholar] [CrossRef]
- Simpson, J.L.; Guest, M. Occupational exposures, smoking and airway inflammation in refractory asthma. BMC Pulm. Med. 2014, 14, 207. [Google Scholar] [CrossRef]
- Carroll, N.; Carello, S. Airway structure and inflammatory cells in fatal attacks of asthma. Eur. Respir. J. 1996, 9, 709–715. [Google Scholar] [CrossRef]
- Sur, S.; Crotty, T.B. Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa? Am. Rev. Respir. Dis. 1993, 148, 713–719. [Google Scholar] [CrossRef]
- Xiong, Y.; Cui, X. BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL-33 production. Allergy 2019, 74, 495–506. [Google Scholar] [CrossRef]
- Gelfand, E.W.; Alam, R. The other side of asthma: Steroid-refractory disease in the absence of TH2-mediated inflammation. J. Allergy Clin. Immunol. 2015, 135, 1196–1198. [Google Scholar] [CrossRef] [PubMed]
- Medoff, B.D.; Tager, A.M. Antibody-antigen interaction in the airway drives early granulocyte recruitment through BLT1. Am. J. Physiol Lung Cell Mol. Physiol. 2006, 290, L170–L178. [Google Scholar] [CrossRef] [PubMed]
- Miyahara, N.; Takeda, K. Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8+ T cells and airway hyperresponsiveness. J. Immunol. 2005, 174, 4979–4984. [Google Scholar] [CrossRef] [PubMed]
- Miyahara, N.; Ohnishi, H. Leukotriene B4 receptor 1 expression on dendritic cells is required for the development of Th2 responses and allergen-induced airway hyperresponsiveness. J. Immunol. 2008, 181, 1170–1178. [Google Scholar] [CrossRef] [PubMed]
- Ohnishi, H.; Miyahara, N. Corticosteroids enhance CD8+ T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1. J. Allergy Clin. Immunol. 2008, 121, 864–871.e4. [Google Scholar] [CrossRef]
- Gelfand, E.W.; Dakhama, A. CD8+ T lymphocytes and leukotriene B4: Novel interactions in the persistence and progression of asthma. J. Allergy Clin. Immunol. 2006, 117, 577–582. [Google Scholar] [CrossRef] [PubMed]
- Evans, D.J.; Barnes, P.J. Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma. Thorax 1996, 51, 1178–1184. [Google Scholar] [CrossRef]
- Asanuma, F.; Kuwabara, K. Effects of leukotriene B4 receptor antagonist, LY293111Na, on antigen-induced bronchial hyperresponsiveness and leukocyte infiltration in sensitized guinea pigs. Inflamm. Res. 2001, 50, 136–141. [Google Scholar] [CrossRef]
- Turner, C.R.; Breslow, R. In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma. J. Clin. Investig. 1996, 97, 381–387. [Google Scholar] [CrossRef]
- Elieh Ali Komi, D.; Bjermer, L. Mast Cell-Mediated Orchestration of the Immune Responses in Human Allergic Asthma: Current Insights. Clin. Rev. Allergy Immunol. 2019, 56, 234–247. [Google Scholar] [CrossRef]
- Kouyama, S.; Otomo-Abe, A. A contraction assay system using primary cultured mouse bronchial smooth muscle cells. Int. Arch. Allergy Immunol. 2013, 161 (Suppl. 2), 93–97. [Google Scholar] [CrossRef]
- Yokomizo, T.; Nakamura, M. Leukotriene receptors as potential therapeutic targets. J. Clin. Investig. 2018, 128, 2691–2701. [Google Scholar] [CrossRef] [PubMed]
- Williams, A.M.; Phaneuf, D.J. Short-term impact of PM2.5 on contemporaneous asthma medication use: Behavior and the value of pollution reductions. Proc. Natl. Acad. Sci. USA 2019, 116, 5246–5253. [Google Scholar] [CrossRef] [PubMed]
- Rabinovitch, N.; Jones, M.J. Cysteinyl Leukotriene Receptor 1 and Health Effects of Particulate Exposure in Asthma. Ann. Am. Thorac. Soc. 2018, 15, S129. [Google Scholar] [CrossRef] [PubMed]
- Fregonese, L.; Silvestri, M. Cysteinyl leukotrienes induce human eosinophil locomotion and adhesion molecule expression via a CysLT1 receptor-mediated mechanism. Clin. Exp. Allergy 2002, 32, 745–750. [Google Scholar] [CrossRef] [PubMed]
- Shirasaki, H.; Kanaizumi, E. Leukotriene D4 induces chemotaxis in human eosinophilc cell line, EoL-1 cells via CysLT1 receptor activation. Heliyon 2017, 3, e00464. [Google Scholar] [CrossRef] [PubMed]
- Chan, C.C.; McKee, K. Eosinophil-eicosanoid interactions: Inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. Eur. J. Pharmacol. 1990, 191, 273–280. [Google Scholar]
- Laitinen, L.A.; Laitinen, A. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet 1993, 341, 989–990. [Google Scholar] [CrossRef]
- Wang, H.B.; Akuthota, P. Airway eosinophil migration into lymph nodes in mice depends on leukotriene C4. Allergy 2017, 72, 927–936. [Google Scholar] [CrossRef]
- Liu, T.; Garofalo, D. Platelet-driven leukotriene C4-mediated airway inflammation in mice is aspirin-sensitive and depends on T prostanoid receptors. J. Immunol. 2015, 194, 5061–5068. [Google Scholar] [CrossRef]
- Ilmarinen, P.; Kankaanranta, H. Eosinophil apoptosis as a therapeutic target in allergic asthma. Basic Clin. Pharmacol. Toxicol. 2014, 114, 109–117. [Google Scholar] [CrossRef] [PubMed]
- Duah, E.; Adapala, R.K. Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT(2) and CysLT(1) receptors. Sci. Rep. 2013, 3, 3274. [Google Scholar] [CrossRef] [PubMed]
- Mauser, P.J.; House, A. Pharmacological characterization of the late phase reduction in lung functions and correlations with microvascular leakage and lung edema in allergen-challenged Brown Norway rats. Pulm. Pharmacol. Ther. 2013, 26, 677–684. [Google Scholar] [CrossRef] [PubMed]
- Parameswaran, K.; Radford, K. Modulation of human airway smooth muscle migration by lipid mediators and Th-2 cytokines. Am. J. Respir. Cell Mol. Biol. 2007, 37, 240–247. [Google Scholar] [CrossRef] [PubMed]
- Dholia, N.; Yadav, U.C.S. Lipid mediator Leukotriene D4-induces airway epithelial cells proliferation through EGFR/ERK1/2 pathway. Prostaglandins Other Lipid Mediat. 2018, 136, 55–63. [Google Scholar] [CrossRef]
- Holgate, S.T.; Peters-Golden, M. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J. Allergy Clin. Immunol. 2003, 111, S18–S34; discussion S34–S16. [Google Scholar] [CrossRef]
- Mehrotra, A.K.; Henderson, W.R., Jr. The role of leukotrienes in airway remodeling. Curr. Mol. Med. 2009, 9, 383–391. [Google Scholar] [CrossRef]
- Matsuda, M.; Tabuchi, Y. Increased expression of CysLT2 receptors in the lung of asthmatic mice and role in allergic responses. Prostaglandins Leukot. Essent. Fatty Acids 2018, 131, 24–31. [Google Scholar] [CrossRef]
- Worrell, K.; Shaw, M.R. A systematic review of the literature on screening for exercise-induced asthma: Considerations for school nurses. J. Sch. Nurs. 2015, 31, 70–76. [Google Scholar] [CrossRef]
- Roche, A.; Ahmareen, O. The role of leukotriene receptor antagonists in exercise induced bronchoconstriction in children. Diagnosis 2014, 1, 213–222. [Google Scholar] [CrossRef]
- Tamada, T.; Ichinose, M. Leukotriene Receptor Antagonists and Antiallergy Drugs. Handb. Exp. Pharmacol. 2017, 237, 153–169. [Google Scholar] [CrossRef] [PubMed]
- Hilberg, T.; Deigner, H.P. Transcription in response to physical stress--clues to the molecular mechanisms of exercise-induced asthma. FASEB J. 2005, 19, 1492–1494. [Google Scholar] [CrossRef] [PubMed]
- Bikov, A.; Gajdocsi, R. Exercise increases exhaled breath condensate cysteinyl leukotriene concentration in asthmatic patients. J. Asthma 2010, 47, 1057–1062. [Google Scholar] [CrossRef] [PubMed]
- Arm, J.P.; Horton, C.E. Enhanced generation of leukotriene B4 by neutrophils stimulated by unopsonized zymosan and by calcium ionophore after exercise-induced asthma. Am. Rev. Respir. Dis. 1988, 138, 47–53. [Google Scholar] [CrossRef] [PubMed]
- Li, K.L.; Lee, A.Y. Aspirin Exacerbated Respiratory Disease: Epidemiology, Pathophysiology, and Management. Med. Sci. 2019, 7, 45. [Google Scholar] [CrossRef] [PubMed]
- Rajan, J.P.; Wineinger, N.E. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J. Allergy Clin. Immunol. 2015, 135, 676–681.e1. [Google Scholar] [CrossRef] [PubMed]
- Sakalar, E.G.; Muluk, N.B. Aspirin-exacerbated respiratory disease and current treatment modalities. Eur. Arch. Otorhinolaryngol. 2017, 274, 1291–1300. [Google Scholar] [CrossRef]
- Kim, S.D.; Cho, K.S. Samter’s Triad: State of the Art. Clin. Exp. Otorhinolaryngol. 2018, 11, 71–80. [Google Scholar] [CrossRef]
- Morales, D.R.; Lipworth, B.J. Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials. J. Allergy Clin. Immunol. 2014, 134, 40–45. [Google Scholar] [CrossRef]
- Steinke, J.W.; Borish, L. Factors driving the aspirin exacerbated respiratory disease phenotype. Am. J. Rhinol. Allergy 2015, 29, 35–40. [Google Scholar] [CrossRef]
- Peters-Golden, M.; Gleason, M.M. Cysteinyl leukotrienes: Multi-functional mediators in allergic rhinitis. Clin. Exp. Allergy 2006, 36, 689–703. [Google Scholar] [CrossRef] [PubMed]
- Milanovic, M.; Terszowski, G. IFN consensus sequence binding protein (Icsbp) is critical for eosinophil development. J. Immunol. 2008, 181, 5045–5053. [Google Scholar] [CrossRef] [PubMed]
- Steinke, J.W.; Liu, L. Prominent role of IFN-gamma in patients with aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 2013, 132, 856–865.e3. [Google Scholar] [CrossRef] [PubMed]
- Liu, T.; Kanaoka, Y. Aspirin-Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway. J. Immunol. 2015, 195, 3537–3545. [Google Scholar] [CrossRef] [PubMed]
- Laidlaw, T.M.; Kidder, M.S. Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 2012, 119, 3790–3798. [Google Scholar] [CrossRef] [PubMed]
- Narayanankutty, A.; Resendiz-Hernandez, J.M. Biochemical pathogenesis of aspirin exacerbated respiratory disease (AERD). Clin. BioChem. 2013, 46, 566–578. [Google Scholar] [CrossRef]
- Laidlaw, T.M.; Boyce, J.A. Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol. Allergy Clin. N. Am. 2013, 33, 195–210. [Google Scholar] [CrossRef]
- Liu, T.; Barrett, N.A. Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. J. Immunol. 2018, 200, 915–927. [Google Scholar] [CrossRef]
- Cingi, C.; Muluk, N.B. Antileukotrienes in upper airway inflammatory diseases. Curr. Allergy Asthma Rep. 2015, 15, 64. [Google Scholar] [CrossRef]
- Hoyte, F.C.L.; Nelson, H.S. Recent advances in allergic rhinitis. F1000Research 2018, 7. [Google Scholar] [CrossRef]
- Figueroa, D.J.; Borish, L. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin. Exp. Allergy 2003, 33, 1380–1388. [Google Scholar] [CrossRef] [PubMed]
- Shirasaki, H.; Kanaizumi, E. Expression and localization of the cysteinyl leukotriene 1 receptor in human nasal mucosa. Clin. Exp. Allergy 2002, 32, 1007–1012. [Google Scholar] [CrossRef] [PubMed]
- Suojalehto, H.; Kinaret, P. Level of Fatty Acid Binding Protein 5 (FABP5) Is Increased in Sputum of Allergic Asthmatics and Links to Airway Remodeling and Inflammation. PLoS ONE 2015, 10, e0127003. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Zhang, J. The efficacy and safety of selective H1-antihistamine versus leukotriene receptor antagonist for seasonal allergic rhinitis: A meta-analysis. PLoS ONE 2014, 9, e112815. [Google Scholar] [CrossRef] [PubMed]
- Liu, G.; Zhou, X. Oral Antihistamines Alone vs in Combination with Leukotriene Receptor Antagonists for Allergic Rhinitis: A Meta-analysis. Otolaryngol. Head Neck Surg. 2018, 158, 450–458. [Google Scholar] [CrossRef] [PubMed]
- Seresirikachorn, K.; Chitsuthipakorn, W. Leukotriene Receptor Antagonist Addition to H1-Antihistamine Is Effective for Treating Allergic Rhinitis: A Systematic Review and Meta-analysis. Am. J. Rhinol. Allergy 2019. [Google Scholar] [CrossRef]
- Cap, P.; Maly, M. Exhaled leukotrienes and bronchial responsiveness to methacholine in patients with seasonal allergic rhinitis. Ann. Allergy Asthma Immunol. 2009, 102, 103–109. [Google Scholar] [CrossRef]
- Weidinger, S.; Novak, N. Atopic dermatitis. Lancet 2016, 387, 1109–1122. [Google Scholar] [CrossRef]
- Vakharia, P.P.; Silverberg, J.I. New and emerging therapies for paediatric atopic dermatitis. Lancet Child. Adolesc. Health 2019, 3, 343–353. [Google Scholar] [CrossRef]
- Nygaard, U.; Vestergaard, C. Emerging Treatment Options in Atopic Dermatitis: Systemic Therapies. Dermatology 2017, 233, 344–357. [Google Scholar] [CrossRef]
- Jin, H.; He, R. Animal models of atopic dermatitis. J. Investig. Dermatol. 2009, 129, 31–40. [Google Scholar] [CrossRef] [PubMed]
- Fogh, K.; Herlin, T. Eicosanoids in skin of patients with atopic dermatitis: Prostaglandin E2 and leukotriene B4 are present in biologically active concentrations. J. Allergy Clin. Immunol. 1989, 83, 450–455. [Google Scholar] [CrossRef]
- Huang, Y.; Chen, G. Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry. J. Proteome Res. 2014, 13, 5715–5723. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, S.; Yasutomo, K. Treatment with DHA/EPA ameliorates atopic dermatitis-like skin disease by blocking LTB4 production. J. Med. Investig. 2016, 63, 187–191. [Google Scholar] [CrossRef] [PubMed]
- Sadik, C.D.; Sezin, T. Leukotrienes orchestrating allergic skin inflammation. Exp. Dermatol. 2013, 22, 705–709. [Google Scholar] [CrossRef] [PubMed]
- Oyoshi, M.K.; He, R. Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity 2012, 37, 747–758. [Google Scholar] [CrossRef] [PubMed]
- Oyoshi, M.K.; He, R. Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proc. Natl. Acad. Sci. USA 2012, 109, 4992–4997. [Google Scholar] [CrossRef]
- Jeon, Y.H.; Min, T.K. A Double-Blind, Randomized, Crossover Study to Compare the Effectiveness of Montelukast on Atopic Dermatitis in Korean Children. Allergy Asthma Immunol. Res. 2016, 8, 305–311. [Google Scholar] [CrossRef]
- Lee, A.Y. Is Montelukast Benefical in Children With Atopic Dermatitis? Allergy Asthma Immunol. Res. 2016, 8, 279–281. [Google Scholar] [CrossRef]
- Roekevisch, E.; Spuls, P.I. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: A systematic review. J. Allergy Clin. Immunol. 2014, 133, 429–438. [Google Scholar] [CrossRef]
- Crow, D.W.; Marsella, R. Double-blinded, placebo-controlled, cross-over pilot study on the efficacy of zileuton for canine atopic dermatitis. Vet. Dermatol. 2001, 12, 189–195. [Google Scholar] [CrossRef] [PubMed]
- Woodmansee, D.P.; Simon, R.A. A pilot study examining the role of zileuton in atopic dermatitis. Ann. Allergy Asthma Immunol. 1999, 83, 548–552. [Google Scholar] [CrossRef]
- Kupczyk, M.; Kuna, P. Targeting the PGD2/CRTH2/DP1 Signaling Pathway in Asthma and Allergic Disease: Current Status and Future Perspectives. Drugs 2017, 77, 1281–1294. [Google Scholar] [CrossRef] [PubMed]
- Hewson, C.A.; Patel, S. Preclinical evaluation of an inhibitor of cytosolic phospholipase A2alpha for the treatment of asthma. J. Pharmacol. Exp. Ther. 2012, 340, 656–665. [Google Scholar] [CrossRef] [PubMed]
- Yanes, D.A.; Mosser-Goldfarb, J.L. Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway. J. Am. Acad. Dermatol. 2018, 78, S71–S75. [Google Scholar] [CrossRef]
- Bielory, L.; Schoenberg, D. Emerging Therapeutics for Ocular Surface Disease. Curr. Allergy Asthma Rep. 2019, 19, 16. [Google Scholar] [CrossRef]
- Spada, C.S.; Woodward, D.F. Leukotrienes cause eosinophil emigration into conjunctival tissue. Prostaglandins 1986, 31, 795–809. [Google Scholar] [CrossRef]
- Andoh, T.; Sakai, K. Involvement of leukotriene B4 in itching in a mouse model of ocular allergy. Exp. Eye Res. 2012, 98, 97–103. [Google Scholar] [CrossRef]
- Pelikan, Z. Mediator profiles in tears during the conjunctival response induced by allergic reaction in the nasal mucosa. Mol. Vis. 2013, 19, 1453–1470. [Google Scholar]
- Dartt, D.A.; Hodges, R.R. Conjunctival goblet cell secretion stimulated by leukotrienes is reduced by resolvins D1 and E1 to promote resolution of inflammation. J. Immunol. 2011, 186, 4455–4466. [Google Scholar] [CrossRef]
- Lambiase, A.; Bonini, S. Montelukast, a leukotriene receptor antagonist, in vernal keratoconjunctivitis associated with asthma. Arch. Ophthalmol. 2003, 121, 615–620. [Google Scholar] [CrossRef] [PubMed]
- Simons, F.E.; Frew, A.J. Risk assessment in anaphylaxis: Current and future approaches. J. Allergy Clin. Immunol. 2007, 120, S2–S24. [Google Scholar] [CrossRef] [PubMed]
- Butterfield, J.H. Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2010, 92, 73–76. [Google Scholar] [CrossRef] [PubMed]
- Maekawa, A.; Austen, K.F. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J. Biol. Chem. 2002, 277, 20820–20824. [Google Scholar] [CrossRef] [PubMed]
- Castells, M.; Butterfield, J. Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management. J. Allergy Clin. Immunol. Pract. 2019, 7, 1097–1106. [Google Scholar] [CrossRef] [PubMed]
- Valent, P.; Akin, C. Mast cell activation syndrome: Importance of consensus criteria and call for research. J. Allergy Clin. Immunol. 2018, 142, 1008–1010. [Google Scholar] [CrossRef] [PubMed]
- Afrin, L.B.; Self, S. Characterization of Mast Cell Activation Syndrome. Am. J. Med. Sci. 2017, 353, 207–215. [Google Scholar] [CrossRef] [PubMed]
- Castells, M.; Austen, K.F. Mastocytosis: Mediator-related signs and symptoms. Int. Arch. Allergy Immunol. 2002, 127, 147–152. [Google Scholar] [CrossRef]
- Sala, A.; Folco, G. Transcellular biosynthesis of eicosanoids. Pharmacol. Rep. 2010, 62, 503–510. [Google Scholar] [CrossRef]
- Denzlinger, C.; Haberl, C. Cysteinyl leukotriene production in anaphylactic reactions. Int. Arch. Allergy Immunol. 1995, 108, 158–164. [Google Scholar] [CrossRef]
- Tagari, P.; Rasmussen, J.B. Comparison of urinary leukotriene E4 and 16-carboxytetranordihydro leukotriene E4 excretion in allergic asthmatics after inhaled antigen. Eicosanoids 1990, 3, 75–80. [Google Scholar] [PubMed]
- Kumlin, M.; Dahlen, B. Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics. Am. Rev. Respir. Dis. 1992, 146, 96–103. [Google Scholar] [CrossRef] [PubMed]
- Armstrong, M.; Liu, A.H. Leukotriene-E4 in human urine: Comparison of on-line purification and liquid chromatography-tandem mass spectrometry to affinity purification followed by enzyme immunoassay. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2009, 877, 3169–3174. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Lueke, A.J.; Meeusen, J.W. Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: A marker of systemic mastocytosis. Clin. BioChem. 2016, 49, 979–982. [Google Scholar] [CrossRef] [PubMed]
- Hagan, J.B.; Laidlaw, T.M. Urinary Leukotriene E4 to Determine Aspirin Intolerance in Asthma: A Systematic Review and Meta-Analysis. J. Allergy Clin. Immunol. Pract. 2017, 5, 990–997.e1. [Google Scholar] [CrossRef] [PubMed]
- Rabinovitch, N.; Silveira, L. The response of children with asthma to ambient particulate is modified by tobacco smoke exposure. Am. J. Respir. Crit. Care Med. 2011, 184, 1350–1357. [Google Scholar] [CrossRef] [PubMed]
- Vachier, I.; Kumlin, M. High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma. Respir. Med. 2003, 97, 1225–1229. [Google Scholar] [CrossRef]
- Divekar, R.; Hagan, J. Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity. J. Allergy Clin. Immunol. Pract. 2016, 4, 665–670. [Google Scholar] [CrossRef]
- Marmarinos, A.; Saxoni-Papageorgiou, P. Urinary leukotriene E4 levels in atopic and non-atopic preschool children with recurrent episodic (viral) wheezing: A potential marker? J. Asthma 2015, 52, 554–559. [Google Scholar] [CrossRef]
- Chiu, C.Y.; Tsai, M.H. Urinary LTE4 levels as a diagnostic marker for IgE-mediated asthma in preschool children: A birth cohort study. PLoS ONE 2014, 9, e115216. [Google Scholar] [CrossRef]
- Kaditis, A.G.; Alexopoulos, E. Urine concentrations of cysteinyl leukotrienes in children with obstructive sleep-disordered breathing. Chest 2009, 135, 1496–1501. [Google Scholar] [CrossRef] [PubMed]
- Satdhabudha, A.; Sritipsukho, P. Urine cysteinyl leukotriene levels in children with sleep disordered breathing before and after adenotonsillectomy. Int. J. Pediatr. Otorhinolaryngol. 2017, 94, 112–116. [Google Scholar] [CrossRef] [PubMed]
- Rabinovitch, N.; Graber, N.J. Urinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthma. J. Allergy Clin. Immunol. 2010, 126, 545–551.e4. [Google Scholar] [CrossRef] [PubMed]
- Rabinovitch, N.; Mauger, D.T. Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma. J. Allergy Clin. Immunol. 2014, 133, 350–356. [Google Scholar] [CrossRef] [PubMed]
- Sunkonkit, K.; Sritippayawan, S. Urinary cysteinyl leukotriene E4 level and therapeutic response to montelukast in children with mild obstructive sleep apnea. Asian Pac. J. Allergy Immunol. 2017, 35, 233–238. [Google Scholar] [CrossRef] [PubMed]
- Kwon, S.Y.; Ro, M. Mediatory roles of leukotriene B4 receptors in LPS-induced endotoxic shock. Sci. Rep. 2019, 9, 5936. [Google Scholar] [CrossRef] [PubMed]
- Zheng, L.X.; Li, K.X. Pain and bone damage in rheumatoid arthritis: Role of leukotriene B4. Clin. Exp. Rheumatol. 2019, in press. [Google Scholar]
- Zhou, J.; Lai, W. BLT1 in dendritic cells promotes Th1/Th17 differentiation and its deficiency ameliorates TNBS-induced colitis. Cell Mol. Immunol. 2018, 15, 1047–1056. [Google Scholar] [CrossRef]
- Madeira, M.F.M.; Queiroz-Junior, C.M. The role of 5-lipoxygenase in Aggregatibacter actinomycetemcomitans-induced alveolar bone loss. J. Clin. Periodontol. 2017, 44, 793–802. [Google Scholar] [CrossRef]
- Hikiji, H.; Ishii, S. A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss. Proc. Natl. Acad. Sci. USA 2009, 106, 21294–21299. [Google Scholar] [CrossRef]
- Sezin, T.; Krajewski, M. The Leukotriene B4 and its Receptor BLT1 Act as Critical Drivers of Neutrophil Recruitment in Murine Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita. J. Investig. Dermatol. 2017, 137, 1104–1113. [Google Scholar] [CrossRef] [PubMed]
- Toda, A.; Terawaki, K. Attenuated Th1 induction by dendritic cells from mice deficient in the leukotriene B4 receptor 1. Biochimie 2010, 92, 682–691. [Google Scholar] [CrossRef] [PubMed]
- Lv, J.; Zou, L. Leukotriene B(4)-leukotriene B(4) receptor axis promotes oxazolone-induced contact dermatitis by directing skin homing of neutrophils and CD8(+) T cells. Immunology 2015, 146, 50–58. [Google Scholar] [CrossRef] [PubMed]
- Sumida, H.; Yanagida, K. Interplay between CXCR2 and BLT1 facilitates neutrophil infiltration and resultant keratinocyte activation in a murine model of imiquimod-induced psoriasis. J. Immunol. 2014, 192, 4361–4369. [Google Scholar] [CrossRef] [PubMed]
- Hegde, B.; Bodduluri, S.R. Inflammasome-Independent Leukotriene B4 Production Drives Crystalline Silica-Induced Sterile Inflammation. J. Immunol. 2018, 200, 3556–3567. [Google Scholar] [CrossRef] [PubMed]
- Sasaki, F.; Koga, T. Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. JCI Insight 2018, 3. [Google Scholar] [CrossRef] [PubMed]
Disease | Roles of the LTB4-BLT1 Pathway | Roles of CysLT Pathways | Anti-leukotriene Standard Therapy in a Clinical Trial Experimentally Effective |
---|---|---|---|
Asthma |
|
| Leukotriene receptor antagonist (LTRA) 5-LO inhibitor (zileuton) |
Neutrophilic asthma |
| BLT1 antagonist (LY293111, CP-105,696) | |
Aspirin-exacerbated respiratory disease; aspirin-sensitive asthma |
| ||
Allergic rhinitis |
| LTRA | |
Atopic dermatitis |
|
| Q301 (zileuton cream)? ZPL-521 (cPLA2 inhibitor ointment)? 5-LO inhibitor (zileuton) |
Allergic conjunctivitis |
|
| LTRA (montelukast) BLT1 antagonist (ONO-4057) 5-LO inhibitor (zileuton) |
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Jo-Watanabe, A.; Okuno, T.; Yokomizo, T. The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. Int. J. Mol. Sci. 2019, 20, 3580. https://doi.org/10.3390/ijms20143580
Jo-Watanabe A, Okuno T, Yokomizo T. The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. International Journal of Molecular Sciences. 2019; 20(14):3580. https://doi.org/10.3390/ijms20143580
Chicago/Turabian StyleJo-Watanabe, Airi, Toshiaki Okuno, and Takehiko Yokomizo. 2019. "The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders" International Journal of Molecular Sciences 20, no. 14: 3580. https://doi.org/10.3390/ijms20143580
APA StyleJo-Watanabe, A., Okuno, T., & Yokomizo, T. (2019). The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders. International Journal of Molecular Sciences, 20(14), 3580. https://doi.org/10.3390/ijms20143580