Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study
Johan Kolmert, Cristina Gómez, David Balgoma, Marcus Sjödin, Johan Bood, Jon R Konradsen, Magnus Ericsson, John-Olof Thörngren, Anna James, Maria Mikus, Ana R Sousa, John H Riley, Stewart Bates, Per S Bakke, Ioannis Pandis, Massimo Caruso, Pascal Chanez, Stephen J Fowler, Thomas Geiser, Peter Howarth, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E Shaw, Richard G Knowles, Cécile T J Holweg, Åsa M Wheelock, Barbro Dahlén, Björn Nordlund, Kjell Alving, Gunilla Hedlin, Kian Fan Chung, Ian M Adcock, Peter J Sterk, Ratko Djukanovic, Sven-Erik Dahlén, Craig E Wheelock, U-BIOPRED Study Group, on behalf of the U-BIOPRED Study Group, H Ahmed, C Auffray, A T Bansal, E H Bel, J Bigler, B Billing, F Baribaud, H Bisgaard, M J Boedigheimer, K Bønnelykke, J Brandsma, P Brinkman, E Bucchioni, D Burg, A Bush, A Chaiboonchoe, C H Compton, J Corfield, D Cunoosamy, A D'Amico, B De Meulder, V J Erpenbeck, D Erzen, K Fichtner, N Fitch, L J Fleming, E Formaggio, U Frey, M Gahlemann, V Goss, Y Guo, S Hashimoto, J Haughney, P W Hekking, T Higenbottam, J M Hohlfeld, A J Knox, N Lazarinis, D Lefaudeux, M J Loza, R Lutter, A Manta, S Masefield, J G Matthews, A Mazein, A Meiser, R J M Middelveld, M Miralpeix, N Mores, C S Murray, J Musial, D Myles, L Pahus, S Pavlidis, A Postle, P Powel, G Praticò, M PuigValls, N Rao, A Roberts, G Roberts, A Rowe, T Sandström, J P R Schofield, W Seibold, A Selby, R Sigmund, F Singer, P J Skipp, M Smicker, K Sun, B Thornton, M Uddin, W M van Aalderen, M van Geest, J Vestbo, N H Vissing, A H Wagener, S S Wagers, Z Weiszhart, S J Wilson, J Östling, H Ahmed, C Auffray, A T Bansal, E H Bel, J Bigler, B Billing, F Baribaud, H Bisgaard, M J Boedigheimer, K Bønnelykke, J Brandsma, P Brinkman, E Bucchioni, D Burg, A Bush, A Chaiboonchoe, C H Compton, J Corfield, D Cunoosamy, A D'Amico, B De Meulder, V J Erpenbeck, D Erzen, K Fichtner, N Fitch, L J Fleming, E Formaggio, U Frey, M Gahlemann, V Goss, Y Guo, S Hashimoto, J Haughney, P W Hekking, T Higenbottam, J M Hohlfeld, A J Knox, N Lazarinis, D Lefaudeux, M J Loza, R Lutter, A Manta, S Masefield, J G Matthews, A Mazein, A Meiser, R J M Middelveld, M Miralpeix, N Mores, C S Murray, J Musial, D Myles, L Pahus, S Pavlidis, A Postle, P Powel, G Praticò, M PuigValls, N Rao, A Roberts, G Roberts, A Rowe, T Sandström, J P R Schofield, W Seibold, A Selby, R Sigmund, F Singer, P J Skipp, M Smicker, K Sun, B Thornton, M Uddin, W M van Aalderen, M van Geest, J Vestbo, N H Vissing, A H Wagener, S S Wagers, Z Weiszhart, S J Wilson, J Östling, Johan Kolmert, Cristina Gómez, David Balgoma, Marcus Sjödin, Johan Bood, Jon R Konradsen, Magnus Ericsson, John-Olof Thörngren, Anna James, Maria Mikus, Ana R Sousa, John H Riley, Stewart Bates, Per S Bakke, Ioannis Pandis, Massimo Caruso, Pascal Chanez, Stephen J Fowler, Thomas Geiser, Peter Howarth, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E Shaw, Richard G Knowles, Cécile T J Holweg, Åsa M Wheelock, Barbro Dahlén, Björn Nordlund, Kjell Alving, Gunilla Hedlin, Kian Fan Chung, Ian M Adcock, Peter J Sterk, Ratko Djukanovic, Sven-Erik Dahlén, Craig E Wheelock, U-BIOPRED Study Group, on behalf of the U-BIOPRED Study Group, H Ahmed, C Auffray, A T Bansal, E H Bel, J Bigler, B Billing, F Baribaud, H Bisgaard, M J Boedigheimer, K Bønnelykke, J Brandsma, P Brinkman, E Bucchioni, D Burg, A Bush, A Chaiboonchoe, C H Compton, J Corfield, D Cunoosamy, A D'Amico, B De Meulder, V J Erpenbeck, D Erzen, K Fichtner, N Fitch, L J Fleming, E Formaggio, U Frey, M Gahlemann, V Goss, Y Guo, S Hashimoto, J Haughney, P W Hekking, T Higenbottam, J M Hohlfeld, A J Knox, N Lazarinis, D Lefaudeux, M J Loza, R Lutter, A Manta, S Masefield, J G Matthews, A Mazein, A Meiser, R J M Middelveld, M Miralpeix, N Mores, C S Murray, J Musial, D Myles, L Pahus, S Pavlidis, A Postle, P Powel, G Praticò, M PuigValls, N Rao, A Roberts, G Roberts, A Rowe, T Sandström, J P R Schofield, W Seibold, A Selby, R Sigmund, F Singer, P J Skipp, M Smicker, K Sun, B Thornton, M Uddin, W M van Aalderen, M van Geest, J Vestbo, N H Vissing, A H Wagener, S S Wagers, Z Weiszhart, S J Wilson, J Östling, H Ahmed, C Auffray, A T Bansal, E H Bel, J Bigler, B Billing, F Baribaud, H Bisgaard, M J Boedigheimer, K Bønnelykke, J Brandsma, P Brinkman, E Bucchioni, D Burg, A Bush, A Chaiboonchoe, C H Compton, J Corfield, D Cunoosamy, A D'Amico, B De Meulder, V J Erpenbeck, D Erzen, K Fichtner, N Fitch, L J Fleming, E Formaggio, U Frey, M Gahlemann, V Goss, Y Guo, S Hashimoto, J Haughney, P W Hekking, T Higenbottam, J M Hohlfeld, A J Knox, N Lazarinis, D Lefaudeux, M J Loza, R Lutter, A Manta, S Masefield, J G Matthews, A Mazein, A Meiser, R J M Middelveld, M Miralpeix, N Mores, C S Murray, J Musial, D Myles, L Pahus, S Pavlidis, A Postle, P Powel, G Praticò, M PuigValls, N Rao, A Roberts, G Roberts, A Rowe, T Sandström, J P R Schofield, W Seibold, A Selby, R Sigmund, F Singer, P J Skipp, M Smicker, K Sun, B Thornton, M Uddin, W M van Aalderen, M van Geest, J Vestbo, N H Vissing, A H Wagener, S S Wagers, Z Weiszhart, S J Wilson, J Östling
Abstract
Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).
Keywords: U-BIOPRED; mass spectrometry; severe asthma; type 2 inflammation; urinary eicosanoid metabolites.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf1.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf2.jpg)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf3.jpg)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf4.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf5.jpg)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf6.jpg)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf7.jpg)
![Figure 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf8.jpg)
![Figure 9.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7781128/bin/rccm.201909-1869OCf9.jpg)
References
- Papi A, Brightling C, Pedersen SE, Reddel HK. Asthma. Lancet. 2018;391:783–800.
- Diamant Z, Vijverberg S, Alving K, Bakirtas A, Bjermer L, Custovic A, et al. Toward clinically applicable biomarkers for asthma: an EAACI position paper. Allergy. 2019;74:1835–1851.
- Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, et al. U-BIOPRED Study Group. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J. 2015;46:1308–1321.
- Dennis EA, Norris PC. Eicosanoid storm in infection and inflammation. Nat Rev Immunol. 2015;15:511–523.
- Dahlén SE, Hedqvist P, Hammarström S, Samuelsson B. Leukotrienes are potent constrictors of human bronchi. Nature. 1980;288:484–486.
- Peters-Golden M, Henderson WR., Jr Leukotrienes. N Engl J Med. 2007;357:1841–1854.
- Dahlén S-E, Malmström K, Nizankowska E, Dahlén B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:9–14.
- Israel E, Rubin P, Kemp JP, Grossman J, Pierson W, Siegel SC, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993;119:1059–1066.
- Bood JR, Sundblad B-M, Delin I, Sjödin M, Larsson K, Anderson SD, et al. Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects. J Appl Physiol (1985) 2015;119:272–279.
- Kolmert J, Fauland A, Fuchs D, Säfholm J, Gómez C, Adner M, et al. Lipid mediator quantification in isolated human and guinea pig airways: an expanded approach for respiratory research. Anal Chem. 2018;90:10239–10248.
- Bauer J, Ripperger A, Frantz S, Ergün S, Schwedhelm E, Benndorf RA. Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation. Br J Pharmacol. 2014;171:3115–3131.
- Milne GL, Yin H, Hardy KD, Davies SS, Roberts LJ., II Isoprostane generation and function. Chem Rev. 2011;111:5973–5996.
- Kumlin M, Dahlén B, Björck T, Zetterström O, Granström E, Dahlén SE. 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.
- O’Sullivan S, Dahlén B, Dahlén SE, Kumlin M. Increased urinary excretion of the prostaglandin D2 metabolite 9 alpha, 11 beta-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. J Allergy Clin Immunol. 1996;98:421–432.
- Gómez C, Gonzalez-Riano C, Barbas C, Kolmert J, Hyung Ryu M, Carlsten C, et al. Quantitative metabolic profiling of urinary eicosanoids for clinical phenotyping. J Lipid Res. 2019;60:1164–1173.
- Sjödin M, Kolmert J, Balgoma D, Delin I, Wheelock CE, Dahlén SE. Urinary LTE4 is a new strong predictor of TH2-driven asthma: Initial data from the Pan-European U-BIOPRED IMI project [abstract] ERS. 2014
- Wheelock C, Kolmert J, Lefaudeux D, Sjödin M, Balgoma D, Sousa A, et al. Non-invasive sub-phenotyping of asthma in the U-BIOPRED study by analysis of urinary lipid mediator excretion patterns [abstract] Am J Respir Crit Care Med. 2016;193:A4632.
- Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–373. [Published erratum appears in Eur Respir J 43:1216.]
- Konradsen JR, Skantz E, Nordlund B, Lidegran M, James A, Ono J, et al. Predicting asthma morbidity in children using proposed markers of Th2-type inflammation. Pediatr Allergy Immunol. 2015;26:772–779.
- Balgoma D, Larsson J, Rokach J, Lawson JA, Daham K, Dahlén B, et al. Quantification of lipid mediator metabolites in human urine from asthma patients by electrospray ionization mass spectrometry: controlling matrix effects. Anal Chem. 2013;85:7866–7874.
- Hanratty CE, Matthews JG, Arron JR, Choy DF, Pavord ID, Bradding P, et al. RASP-UK (Refractory Asthma Stratification Programme) Consortium. A randomised pragmatic trial of corticosteroid optimization in severe asthma using a composite biomarker algorithm to adjust corticosteroid dose versus standard care: study protocol for a randomised trial. Trials. 2018;19:5.
- Yang M, Kohler M, Heyder T, Forsslund H, Garberg HK, Karimi R, et al. Long-term smoking alters abundance of over half of the proteome in bronchoalveolar lavage cell in smokers with normal spirometry, with effects on molecular pathways associated with COPD. Respir Res. 2018;19:40.
- Hayashi H, Mitsui C, Nakatani E, Fukutomi Y, Kajiwara K, Watai K, et al. Omalizumab reduces cysteinyl leukotriene and 9α,11β-prostaglandin F2 overproduction in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2016;137:1585–1587, e4.
- Grootendorst DC, Dahlén S-E, Van Den Bos JW, Duiverman EJ, Veselic-Charvat M, Vrijlandt EJLE, et al. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy. 2001;31:400–408.
- Daham K, James A, Balgoma D, Kupczyk M, Billing B, Lindeberg A, et al. Effects of selective COX-2 inhibition on allergen-induced bronchoconstriction and airway inflammation in asthma. J Allergy Clin Immunol. 2014;134:306–313.
- Taylor GW, Taylor I, Black P, Maltby NH, Turner N, Fuller RW, et al. Urinary leukotriene E4 after antigen challenge and in acute asthma and allergic rhinitis. Lancet. 1989;1:584–588.
- Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med. 1986;315:983–989.
- Gülen T, Möller Westerberg C, Lyberg K, Ekoff M, Kolmert J, Bood J, et al. Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis. Clin Exp Allergy. 2017;47:909–917.
- Seyberth HW, Sweetman BJ, Frolich JC, Oates JA. Quantifications of the major urinary metabolite of the E prostaglandins by mass spectrometry: evaluation of the method’s application to clinical studies. Prostaglandins. 1976;11:381–397.
- Lupinetti MD, Sheller JR, Catella F, Fitzgerald GA. Thromboxane biosynthesis in allergen-induced bronchospasm: evidence for platelet activation. Am Rev Respir Dis. 1989;140:932–935.
- Capra V, Rovati GE, Mangano P, Buccellati C, Murphy RC, Sala A. Transcellular biosynthesis of eicosanoid lipid mediators. Biochim Biophys Acta. 2015;1851:377–382.
- Säfholm J, Manson ML, Bood J, Delin I, Orre A-C, Bergman P, et al. Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor. J Allergy Clin Immunol. 2015;136:1232–9.e1.
- Cahill KN, Cui J, Kothari P, Murphy K, Raby BA, Singer J, et al. Unique effect of aspirin therapy on biomarkers in aspirin-exacerbated respiratory disease: a prospective trial. Am J Respir Crit Care Med. 2019;200:704–711.
- Maric J, Ravindran A, Mazzurana L, Björklund ÅK, Van Acker A, Rao A, et al. Prostaglandin E2 suppresses human group 2 innate lymphoid cell function. J Allergy Clin Immunol. 2018;141:1761–1773, e6.
- Manso G, Baker AJ, Taylor IK, Fuller RW. In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur Respir J. 1992;5:712–716.
- Gyllfors P, Dahlén S-E, Kumlin M, Larsson K, Dahlén B. Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate. J Allergy Clin Immunol. 2006;118:78–83.
- Sebaldt RJ, Sheller JR, Oates JA, Roberts LJ, II, FitzGerald GA. Inhibition of eicosanoid biosynthesis by glucocorticoids in humans. Proc Natl Acad Sci U S A. 1990;87:6974–6978.
- Dworski R, Fitzgerald GA, Oates JA, Sheller JR. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med. 1994;149:953–959.
- Vachier I, Kumlin M, Dahlén SE, Bousquet J, Godard P, Chanez P. High levels of urinary leukotriene E4 excretion in steroid treated patients with severe asthma. Respir Med. 2003;97:1225–1229.
- Hayashi H, Fukutomi Y, Mitsui C, Kajiwara K, Watai K, Kamide Y, et al. Omalizumab for aspirin hypersensitivity and leukotriene overproduction in aspirin-exacerbated respiratory disease: a randomized controlled trial. Am J Respir Crit Care Med. 2020;201:1488–1498.
- Uematsu T, Kanamaru M, Kosuge K, Hara K, Uchiyama N, Takenaga N, et al. Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK-0591, in healthy volunteers. Br J Clin Pharmacol. 1995;40:59–66.
- Dahlén B, Nizankowska E, Szczeklik A, Zetterström O, Bochenek G, Kumlin M, et al. 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.
- Carmella SG, Heskin AK, Tang MK, Jensen J, Luo X, Le CT, et al. Longitudinal stability in cigarette smokers of urinary eicosanoid biomarkers of oxidative damage and inflammation. PLoS One. 2019;14:e0215853.
- Inoue Y, Izuhara K, Ohta S, Ono J, Shimojo N. No increase in the serum periostin level is detected in elementary school-age children with allergic diseases. Allergol Int. 2015;64:289–290.
- van ’t Erve TJ, Kadiiska MB, London SJ, Mason RP. Classifying oxidative stress by F2-isoprostane levels across human diseases: a meta-analysis. Redox Biol. 2017;12:582–599.
- Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657–2669.
- Duvall MG, Bruggemann TR, Levy BD. Bronchoprotective mechanisms for specialized pro-resolving mediators in the resolution of lung inflammation. Mol Aspects Med. 2017;58:44–56.
- Gijón MA, Almstrand A-C, Johnson CA, Murphy RC, Zarini S. Identification of metabolites of maresin 1 in human neutrophils [abstract] FASEB J. 2017;31:lb230.
- Balas L, Risé P, Gandrath D, Rovati G, Bolego C, Stellari F, et al. Rapid metabolization of protectin D1 by β-oxidation of its polar head chain. J Med Chem. 2019;62:9961–9975.
- Kolmert J, Forngren B, Lindberg J, Öhd J, Åberg KM, Nilsson G, et al. A quantitative LC/MS method targeting urinary 1-methyl-4-imidazoleacetic acid for safety monitoring of the global histamine turnover in clinical studies. Anal Bioanal Chem. 2014;406:1751–1762.
Source: PubMed