Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Département de Médecine, Faculté de Médecine, Université Laval, Quebec City, QC G1V 4G5, Canada.
Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Quebec City, QC G1V 0A6, Canada.
Cells. 2022 Jan 2;11(1):141. doi: 10.3390/cells11010141.
High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C and LTB in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.
高嗜酸性粒细胞 (EOS) 计数是嗜酸性粒细胞性哮喘的一个关键特征。EOS 通过产生几种脂质介质显著影响哮喘反应。人们利用小鼠来希望确定治疗哮喘的新的药理学靶点。然而，许多在小鼠中确定的靶点并没有转化为临床应用，这突显了这两个物种之间存在关键差异。在这项研究中，我们比较了人类 (h) 和小鼠 (m) EOS 生物合成源自花生四烯酸 (AA)、二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 的关键生物活性脂质的能力。hEOS 从健康受试者和轻度哮喘患者的血液中分离出来，而 mEOS 则从骨髓中分化出来。用脂肪酸处理 EOS，并通过 LC-MS/MS 评估脂质介质生物合成。我们发现 hEOS 以 5:1 的比例生物合成白三烯 (LT) C 和 LTB，而 mEOS 几乎专门生物合成 LTB。15-脂氧合酶 (LO) 代谢物 15-HETE 和 12-HETE 的生物合成也不同，hEOS 的 15-HETE:12-HETE 比值为 6.3，而 mEOS 为 0.727。EOS 生物合成了一些特殊的促解决介质，并且 mEOS 的水平比 hEOS 高 9 倍。相比之下，hEOS 从 EPA 和 DHA 产生了大量的内源性大麻素 2-花生四烯酰甘油 (2-AG) 及其同系物，而 mEOS 中的这种生物合成途径的显著程度低至约 100 倍。我们的数据表明，hEOS 和 mEOS 生物合成相同的脂质介质，但数量不同。与哮喘患者相比，小鼠模型可能具有增强的 LTB 和特殊的促解决介质参与，以及减弱的内源性大麻素 2-花生四烯酰甘油及其同系物的影响。
