Radical-induced lipid oxidation produces a torrent of leukotriene-like agonists in severe asthma

We discovered a family of cysteinyl leukotriene (CysLT)-like biomolecules, pseudo leukotrienes (øLTs), produced through radical-induced oxidation of arachidonate.

We sought to test hypotheses that øLT levels are elevated in asthma and that øLTs induce CysLT receptor-dependent inflammatory signaling in bronchial epithelial cells.

Liquid chromatography-tandem mass spectrometry analysis determined levels of øLTs in urine from human subjects and in lung samples from mice exposed to house dust mite extract. Inflammatory signaling induced by øLTs and CysLTs in human bronchial epithelial cells were compared.

Mean urinary øLTC and øLTD concentrations were elevated 4-fold (P = .004) to 5-fold (P = .0015) in severe asthma. Adding øLTC+øLTD improved the statistical significance of the differences between controls and moderate (P = .0004) or severe (P = .00008) asthma. Pulmonary øLT concentrations were elevated 100% in mice after allergen exposure. øLTs induced phosphorylation of extracellular signal-regulated kinase and protein kinase B (Akt) in bronchial epithelial cells, which was inhibited by CysLT receptor antagonists.

Urinary øLTs are new biomarkers that may facilitate noninvasive assessment of asthma severity and the efficacy of therapeutic measures. Presumably øLTs contribute to CysLT receptor-mediated inflammation through CysLT-like inflammatory biological activities previously ascribed uniquely to CysLTs. øLTs provide a mechanistic link between radical-induced biochemistry, activation of the extracellular signal-regulated kinase/Akt pathway, and asthma. These discoveries require re-examination of long-held disease paradigms for the involvement of CysLTs in asthma pathology and reconsideration of the mechanistic basis for the efficacy of CysLT receptor antagonists for ameliorating chronic asthma. Inhibiting the biosynthesis of øLTs may provide new therapeutic strategies for preventing asthmatic inflammation.