自由基诱导的脂质氧化在严重哮喘中产生大量类白三烯激动剂
2026/02/02
摘要
背景：我们发现了一类通过自由基诱导花生四烯酸氧化产生的类半胱氨酰白三烯（CysLT）生物分子——伪白三烯（øLTs）。
目的：我们旨在验证以下假设：哮喘患者体内øLT水平升高，并且øLTs能够在支气管上皮细胞中诱导依赖于CysLT受体的炎症信号传导。
方法：通过液相色谱-串联质谱分析，测定人类受试者尿液样本以及暴露于屋尘螨提取物的小鼠肺组织样本中øLTs的水平。比较øLTs和CysLTs在人支气管上皮细胞中诱导的炎症信号。
结果：严重哮喘患者尿液中øLTC和øLTD的平均浓度分别升高了4倍（P=0.004）和5倍（P=0.0015）。加入øLTC+øLTD后，对照组与中度哮喘（P=0.0004）或严重哮喘（P=0.00008）之间的差异统计学显著性得到改善。过敏原暴露后，小鼠肺组织中øLT浓度升高了100%。øLTs能够诱导支气管上皮细胞中细胞外信号调节激酶和蛋白激酶B（Akt）的磷酸化，这一过程可被CysLT受体拮抗剂抑制。
结论：尿液中的øLTs是新型生物标志物，可能有助于无创评估哮喘严重程度和治疗措施的有效性。推测øLTs通过此前被认为仅由CysLTs介导的类CysLT炎症生物活性，参与了CysLT受体介导的炎症反应。øLTs在自由基诱导的生物化学、细胞外信号调节激酶/Akt通路的激活以及哮喘之间建立了机制联系。这些发现要求重新审视长期以来关于CysLTs参与哮喘病理的疾病范式，并重新评估CysLT受体拮抗剂缓解慢性哮喘的疗效的机制基础。抑制øLTs的生物合成可能为预防哮喘炎症提供新的治疗策略。CysLTs受体拮抗剂通过阻断CysLTs的生物合成来预防哮喘炎症。这种作用机制可能为开发新的治疗策略提供信息。CysLTs的生物合成可能为预防哮喘炎症提供新的治疗策略。
Radical-induced lipid oxidation produces a torrent of leukotriene-like agonists in severe asthma
S. Y. Liu, M. Linetsky, A. Hite, Y. S. Cheng, M. Miyagi, S. C. Zhu, et al.
Abstract
BACKGROUND:We discovered a family of cysteinyl leukotriene (CysLT)-like biomolecules, pseudo leukotrienes (øLTs), produced through radical-induced oxidation of arachidonate.
OBJECTIVE: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.
METHODS: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.
RESULTS: Mean urinary øLTC and øLTD concentrations were elevated 4-fold (P=0.004) to 5-fold (P=0.0015) in severe asthma. Adding øLTC+øLTD improved the statistical significance of the differences between controls and moderate (P=0.0004) or severe (P=0.00008) 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.
CONCLUSION: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.
背景：我们发现了一类通过自由基诱导花生四烯酸氧化产生的类半胱氨酰白三烯（CysLT）生物分子——伪白三烯（øLTs）。
目的：我们旨在验证以下假设：哮喘患者体内øLT水平升高，并且øLTs能够在支气管上皮细胞中诱导依赖于CysLT受体的炎症信号传导。
方法：通过液相色谱-串联质谱分析，测定人类受试者尿液样本以及暴露于屋尘螨提取物的小鼠肺组织样本中øLTs的水平。比较øLTs和CysLTs在人支气管上皮细胞中诱导的炎症信号。
结果：严重哮喘患者尿液中øLTC和øLTD的平均浓度分别升高了4倍（P=0.004）和5倍（P=0.0015）。加入øLTC+øLTD后，对照组与中度哮喘（P=0.0004）或严重哮喘（P=0.00008）之间的差异统计学显著性得到改善。过敏原暴露后，小鼠肺组织中øLT浓度升高了100%。øLTs能够诱导支气管上皮细胞中细胞外信号调节激酶和蛋白激酶B（Akt）的磷酸化，这一过程可被CysLT受体拮抗剂抑制。
结论：尿液中的øLTs是新型生物标志物，可能有助于无创评估哮喘严重程度和治疗措施的有效性。推测øLTs通过此前被认为仅由CysLTs介导的类CysLT炎症生物活性，参与了CysLT受体介导的炎症反应。øLTs在自由基诱导的生物化学、细胞外信号调节激酶/Akt通路的激活以及哮喘之间建立了机制联系。这些发现要求重新审视长期以来关于CysLTs参与哮喘病理的疾病范式，并重新评估CysLT受体拮抗剂缓解慢性哮喘的疗效的机制基础。抑制øLTs的生物合成可能为预防哮喘炎症提供新的治疗策略。CysLTs受体拮抗剂通过阻断CysLTs的生物合成来预防哮喘炎症。这种作用机制可能为开发新的治疗策略提供信息。CysLTs的生物合成可能为预防哮喘炎症提供新的治疗策略。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（J Allergy Clin Immunol. 2026 Jan;157(1):99-109.DOI: 10.1016/j.jaci.2025.09.027）
（J Allergy Clin Immunol. 2026 Jan;157(1):99-109.DOI: 10.1016/j.jaci.2025.09.027）
Radical-induced lipid oxidation produces a torrent of leukotriene-like agonists in severe asthma
S. Y. Liu, M. Linetsky, A. Hite, Y. S. Cheng, M. Miyagi, S. C. Zhu, et al.
Abstract
BACKGROUND:We discovered a family of cysteinyl leukotriene (CysLT)-like biomolecules, pseudo leukotrienes (øLTs), produced through radical-induced oxidation of arachidonate.
OBJECTIVE: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.
METHODS: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.
RESULTS: Mean urinary øLTC and øLTD concentrations were elevated 4-fold (P=0.004) to 5-fold (P=0.0015) in severe asthma. Adding øLTC+øLTD improved the statistical significance of the differences between controls and moderate (P=0.0004) or severe (P=0.00008) 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.
CONCLUSION: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.
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城市儿童免疫发育及其与环境暴露、过敏致敏和哮喘的关系
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在ATLANTIS队列中通过聚类分析识别不同的哮喘表型
