SEVERE asthma was shown to involve a previously unrecognised wave of inflammatory lipid mediators, offering a potential new biomarker for assessing disease severity and treatment response.
Researchers identified a family of cysteinyl leukotriene-like molecules, termed pseudo leukotrienes, generated through radical-induced lipid oxidation. These compounds were found at markedly higher levels in patients with severe asthma and were shown to activate inflammatory signalling pathways long associated with asthma pathology.
Severe asthma biomarkers reveal hidden inflammatory activity
Asthma is a chronic inflammatory airway disease affecting more than 300 million people worldwide, with severe asthma representing a disproportionate burden of morbidity and healthcare use. Although cysteinyl leukotrienes have long been implicated in airway inflammation and bronchoconstriction, their precise sources and mechanisms of action have remained incompletely understood.
In this study, investigators analysed urine samples from human participants and lung tissue from mouse models using liquid chromatography–tandem mass spectrometry. Mean urinary concentrations of two pseudo leukotrienes were elevated four- to five-fold in individuals with severe asthma compared with controls (P=0.004 and P=0.0015). When combined, these markers significantly improved discrimination between controls and patients with moderate or severe disease.
Parallel animal experiments showed that pulmonary pseudo leukotriene concentrations doubled following allergen exposure. In cultured human bronchial epithelial cells, these molecules triggered phosphorylation of extracellular signal-regulated kinase and protein kinase B, key components of inflammatory signalling. These effects were inhibited by cysteinyl leukotriene receptor antagonists, indicating that pseudo leukotrienes act through the same receptor pathways as classical leukotrienes.
The findings suggested that severe asthma biomarkers derived from lipid oxidation may account for inflammatory activity previously attributed solely to enzymatically produced leukotrienes, potentially explaining the variable clinical efficacy of leukotriene receptor antagonists.
Clinical implications and future directions
Rather than simply expanding the list of inflammatory mediators in asthma, the study established pseudo leukotrienes as a previously unrecognised mechanistic link between radical-driven lipid biochemistry and cysteinyl leukotriene receptor–dependent inflammation.
The authors described these molecules as “unknown unknowns” that may have confounded previous disease models. Because pseudo leukotrienes were detectable in human urine and shared biological activity with classical leukotrienes, they may represent a dominant driver of inflammation in severe disease.
The work also reframed the asthmatic airway as an environment that favours radical chemistry, characterised by elevated reactive oxygen species, depleted antioxidant proteins, and reduced airway glutathione. Monitoring urinary pseudo leukotrienes could therefore support earlier disease detection, assessment of therapeutic efficacy, and preventative correction of impaired antioxidant defences before asthma progresses.
Reference
Liu SY et al. Radical-induced lipid oxidation produces a torrent of leukotriene-like agonists in severe asthma. J Allergy Clin Immunol. 2026;157(1):99-109.
