Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma

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; Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)

doi:10.1183/23120541.01089-2024

Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma

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^*, Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

25 Downloads (Pure)

Abstract

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: F_ENO≥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.

Original language	English
Article number	01089-2024
Number of pages	15
Journal	ERJ Open Research
Volume	11
Issue number	4
DOIs	https://doi.org/10.1183/23120541.01089-2024
Publication status	Published - 01 Jul 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

urinary thromboxane
isoprostane levels
symptom-high
asthma

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Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma
Copyright 2025 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Eastwood, M. C., Busby, J., Kolmert, J., Zurita, J., Dahlén, S.-E., McDowell, P. J., Bradley, J., Jackson, D., Pavord, I., Djukanovic, R., Arron, J., Bradding, P., Brightling, C., Chaudhuri, R., Cowan, D., Fowler, S., Hardman, T. C., Holweg, C., Lordan, J., ... Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK) (2025). Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma. ERJ Open Research, 11(4), Article 01089-2024. https://doi.org/10.1183/23120541.01089-2024

@article{09cad77614c9464296e93a2227057684,

title = "Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma",

abstract = "Background ∼5{\textendash}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{\texttimes}109 cells·L−1; versus T2-high: FENO ≥20 ppb and BEC ≥0.15{\texttimes}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. ",

keywords = "urinary thromboxane, isoprostane levels, symptom-high, asthma",

author = "Eastwood, \{Matthew Chad\} and John Busby and Johan Kolmert and Javier Zurita and Sven-Erik Dahl{\'e}n and McDowell, \{Pamela Jane\} and Judy Bradley and David Jackson and Ian Pavord and Ratko Djukanovic and Joseph Arron and Peter Bradding and Chris Brightling and Rekha Chaudhuri and Douglas Cowan and Stephen Fowler and Hardman, \{Timothy Colin\} and Cecile Holweg and James Lordan and Adel Mansur and Douglas Robinson and Wheelock, \{Craig E.\} and Liam Heaney and \{Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)\}",

year = "2025",

month = jul,

day = "1",

doi = "10.1183/23120541.01089-2024",

language = "English",

volume = "11",

journal = "ERJ Open Research",

issn = "2312-0541",

publisher = "European Respiratory Society",

number = "4",

}

Eastwood, MC, Busby, J, Kolmert, J, Zurita, J, Dahlén, S-E, McDowell, PJ , Bradley, J, Jackson, D, Pavord, I, Djukanovic, R, Arron, J, Bradding, P, Brightling, C, Chaudhuri, R, Cowan, D, Fowler, S, Hardman, TC, Holweg, C, Lordan, J, Mansur, A, Robinson, D, Wheelock, CE, Heaney, L & Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK) 2025, 'Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma', ERJ Open Research, vol. 11, no. 4, 01089-2024. https://doi.org/10.1183/23120541.01089-2024

TY - JOUR

T1 - Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma

AU - Eastwood, Matthew Chad

AU - Busby, John

AU - Kolmert, Johan

AU - Zurita, Javier

AU - Dahlén, Sven-Erik

AU - McDowell, Pamela Jane

AU - Bradley, Judy

AU - Jackson, David

AU - Pavord, Ian

AU - Djukanovic, Ratko

AU - Arron, Joseph

AU - Bradding, Peter

AU - Brightling, Chris

AU - Chaudhuri, Rekha

AU - Cowan, Douglas

AU - Fowler, Stephen

AU - Hardman, Timothy Colin

AU - Holweg, Cecile

AU - Lordan, James

AU - Mansur, Adel

AU - Robinson, Douglas

AU - Wheelock, Craig E.

AU - Heaney, Liam

AU - Investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)

PY - 2025/7/1

Y1 - 2025/7/1

N2 - 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.

AB - 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.

KW - urinary thromboxane

KW - isoprostane levels

KW - symptom-high

KW - asthma

U2 - 10.1183/23120541.01089-2024

DO - 10.1183/23120541.01089-2024

M3 - Article

SN - 2312-0541

VL - 11

JO - ERJ Open Research

JF - ERJ Open Research

IS - 4

M1 - 01089-2024

ER -

Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma

Abstract

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Keywords

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