Matthew Chad Eastwood, John Busby, Johan Kolmert, Javier Zurita, Sven-Erik Dahlén, Pamela Jane McDowell, Judy Bradley, David Jackson, Ian Pavord, Ratko Djukanovic, Joseph Arron, Peter Bradding, Chris Brightling, Rekha Chaudhuri, Douglas Cowan, Stephen Fowler, Timothy Colin Hardman, Cecile Holweg, James Lordan, Adel Mansur, Douglas Robinson, Craig E Wheelock, Liam Heaney
{"title":"尿血栓素和异前列腺素水平在症状高的t2生物标志物低的严重哮喘中升高。","authors":"Matthew Chad Eastwood, John Busby, Johan Kolmert, Javier Zurita, Sven-Erik Dahlén, Pamela Jane McDowell, Judy Bradley, David Jackson, Ian Pavord, Ratko Djukanovic, Joseph Arron, Peter Bradding, Chris Brightling, Rekha Chaudhuri, Douglas Cowan, Stephen Fowler, Timothy Colin Hardman, Cecile Holweg, James Lordan, Adel Mansur, Douglas Robinson, Craig E Wheelock, Liam Heaney","doi":"10.1183/23120541.01089-2024","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status.</p><p><strong>Methods: </strong>Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (<i>F</i> <sub>ENO</sub>) <20 ppb and blood eosinophil count (BEC) <0.15×10<sup>9</sup> cells·L<sup>-1</sup>; <i>versus</i> T2-high: <i>F</i> <sub>ENO</sub> ≥20 ppb and BEC ≥0.15×10<sup>9</sup> cells·L<sup>-1</sup>), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; <i>versus</i> symptom-high: ACQ-7 ≥1.5) and obesity.</p><p><strong>Results: </strong>Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high <i>versus</i> symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high <i>versus</i> symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E<sub>4</sub> levels (LTE<sub>4</sub>) were elevated in T2-high <i>versus</i> T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05).</p><p><strong>Conclusion: </strong>Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.</p>","PeriodicalId":11739,"journal":{"name":"ERJ Open Research","volume":"11 4","pages":""},"PeriodicalIF":4.0000,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378740/pdf/","citationCount":"0","resultStr":"{\"title\":\"Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma.\",\"authors\":\"Matthew Chad Eastwood, John Busby, Johan Kolmert, Javier Zurita, Sven-Erik Dahlén, Pamela Jane McDowell, Judy Bradley, David Jackson, Ian Pavord, Ratko Djukanovic, Joseph Arron, Peter Bradding, Chris Brightling, Rekha Chaudhuri, Douglas Cowan, Stephen Fowler, Timothy Colin Hardman, Cecile Holweg, James Lordan, Adel Mansur, Douglas Robinson, Craig E Wheelock, Liam Heaney\",\"doi\":\"10.1183/23120541.01089-2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status.</p><p><strong>Methods: </strong>Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (<i>F</i> <sub>ENO</sub>) <20 ppb and blood eosinophil count (BEC) <0.15×10<sup>9</sup> cells·L<sup>-1</sup>; <i>versus</i> T2-high: <i>F</i> <sub>ENO</sub> ≥20 ppb and BEC ≥0.15×10<sup>9</sup> cells·L<sup>-1</sup>), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; <i>versus</i> symptom-high: ACQ-7 ≥1.5) and obesity.</p><p><strong>Results: </strong>Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high <i>versus</i> symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high <i>versus</i> symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E<sub>4</sub> levels (LTE<sub>4</sub>) were elevated in T2-high <i>versus</i> T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05).</p><p><strong>Conclusion: </strong>Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.</p>\",\"PeriodicalId\":11739,\"journal\":{\"name\":\"ERJ Open Research\",\"volume\":\"11 4\",\"pages\":\"\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-08-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12378740/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ERJ Open Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1183/23120541.01089-2024\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/7/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ERJ Open Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1183/23120541.01089-2024","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/7/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma.
Background: ∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status.
Methods: Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (FENO) <20 ppb and blood eosinophil count (BEC) <0.15×109 cells·L-1; versus T2-high: FENO ≥20 ppb and BEC ≥0.15×109 cells·L-1), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; versus symptom-high: ACQ-7 ≥1.5) and obesity.
Results: Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high versus symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high versus symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E4 levels (LTE4) were elevated in T2-high versus T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05).
Conclusion: Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.
期刊介绍：
ERJ Open Research is a fully open access original research journal, published online by the European Respiratory Society. The journal aims to publish high-quality work in all fields of respiratory science and medicine, covering basic science, clinical translational science and clinical medicine. The journal was created to help fulfil the ERS objective to disseminate scientific and educational material to its members and to the medical community, but also to provide researchers with an affordable open access specialty journal in which to publish their work.
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