Eosinophils synthesize trihydroxyoctadecenoic acids (TriHOMEs) via a 15-lipoxygenase dependent process.
嗜酸性粒细胞通过 15-脂氧合酶依赖性过程合成三羟基十八烯酸 (trihos)。
- 作者列表："Fuchs D","Tang X","Johnsson AK","Dahlén SE","Hamberg M","Wheelock CE
:Trihydroxyoctadecenoic acids (TriHOMEs) are linoleic acid-derived lipid mediators reported to be dysregulated in obstructive lung disease. In contrast to many other oxylipins, TriHOME biosynthesis in humans is still poorly understood. The association of TriHOMEs with inflammation prompted the current investigation into the ability of human granulocytes to synthesize the 16 different 9,10,13-TriHOME and 9,12,13-TriHOME isomers and of the TriHOME biosynthetic pathway. Following incubation with linoleic acid, eosinophils and (to a lesser extent) the mast cell line LAD2, but not neutrophils, formed TriHOMEs. Stereochemical analysis revealed that TriHOMEs produced by eosinophils predominantly evidenced the 13(S) configuration, suggesting 15-lipoxygenase (15-LOX)-mediated synthesis. TriHOME formation was blocked following incubation with the 15-LOX inhibitor BLX-3887 and was shown to be largely independent of soluble epoxide hydrolase and cytochrome P450 activities. TriHOME synthesis was abolished when linoleic acid was replaced with 13-HODE, but increased in incubations with 13-HpODE, indicating the intermediary role of epoxy alcohols in TriHOME formation. In contrast to eosinophils, LAD2 cells formed TriHOMEs having predominantly the 13(R) configuration, demonstrating that there are multiple synthetic routes for TriHOME formation. These findings provide for the first-time insight into the synthetic route of TriHOMEs in humans and expand our understanding of their formation in inflammatory diseases.
: 三羟基十八烯酸 (trihome) 是亚油酸衍生的脂质介质，据报道在阻塞性肺病中调节失调。与许多其他氧脂素相比，人类的 TriHOME 生物合成仍知之甚少。TriHOME 与炎症的关联促使目前研究人类粒细胞合成 16 种不同的 9 、 10 、 13-TriHOME 和 9 、 12 、 13-TriHOME 异构体以及 TriHOME 生物合成途径的能力。与亚油酸孵育后，嗜酸性粒细胞和 (在较小程度上) 肥大细胞系 LAD2，而不是嗜中性粒细胞，形成了三重体。立体化学分析发现，嗜酸性粒细胞产生的 trihome 主要证明了 13 (S) 构型，提示 15-脂氧合酶 (15-LOX) 介导的合成。用 15-LOX 抑制剂 BLX-3887 孵育后，TriHOME 形成被阻断，并被证明在很大程度上独立于可溶性环氧化物水解酶和细胞色素 P450 活性。当亚油酸被 13-HODE 取代时，TriHOME 合成被废除，但在与 13-HpODE 的孵育中增加，表明环氧醇在 TriHOME 形成中的中介作用。与嗜酸性粒细胞相比，LAD2 细胞形成了以 13 (R) 构型为主的 TriHOME，证明了 TriHOME 形成有多种合成路线。这些发现为首次深入了解人体内 TriHOMEs 的合成途径提供了依据，并扩展了我们对其在炎症性疾病中形成的理解。
METHODS::Translation of genomic alterations to protein changes in chronic obstructive pulmonary disease (COPD) is largely unexplored. Using integrated proteomic and RNA sequencing analysis of COPD and control lung tissues, we identified a protein signature in COPD characterised by extracellular matrix changes and a potential regulatory role for SUMO2. Furthermore, we identified 61 differentially expressed novel, non-reference, peptides in COPD compared with control lungs. This included two peptides encoding for a new splice variant of SORBS1, of which the transcript usage was higher in COPD compared with control lungs. These explorative findings and integrative proteogenomic approach open new avenues to further unravel the pathology of COPD.