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 ( ) <20 ppb and blood eosinophil count (BEC) <0.15×10 cells·L; T2-high: ≥20 ppb and BEC ≥0.15×10 cells·L), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; 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 symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E levels (LTE) were elevated in T2-high 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.

Citation

Eastwood MC, Busby J, Kolmert J, Zurita J, Dahlén SE, 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 Programme. Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma. ERJ Open Res. 2025 Aug 26;11(4):01089-2024. doi: 10.1183/23120541.01089-2024.

Type

Article