Homann Julia, Suo Jing, Schmidt Mike, de Bruin Natasja, Scholich Klaus, Geisslinger Gerd, Ferreirós Nerea
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group TMP, Frankfurt, Germany.
PLoS One. 2015 Nov 23;10(11):e0143141. doi: 10.1371/journal.pone.0143141. eCollection 2015.
The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti-inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 μM, 5 μL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi-LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid.
多形核中性粒细胞（PMN）的激活和浸润是炎症过程中的关键步骤。PMN介导的炎症受到抗炎和促消退机制的限制，包括特殊的促消退脂质介质（SPM）。我们在恶唑酮（OXA）诱导的皮肤炎症超敏反应模型中，研究了15-表-脂氧素A4（15-epi-LXA4）对炎症以及前列腺素、白三烯B4和各种羟基二十碳四烯酸及SPM等促炎介质生物合成的影响。与用赋形剂处理的皮肤相比，在OXA激发后24小时，皮下注射15-epi-LXA4（100 μM，5 μL）可显著（P < 0.05）减轻皮肤炎症。未观察到对前列腺素或白三烯B4生物合成的显著影响，而在经15-epi-LXA4处理的皮肤区域，15S-羟基二十碳四烯酸水平显著（P < 0.05）降低。尽管使用了经过充分验证的分析程序，但在生物样品中未检测到SPM。为了探究缺乏分析信号的原因，我们尝试通过将SPM（脂氧素、消退素、maresin和保护素）皮下注射到小鼠皮肤中，并研究这些化合物的体内可用性和分布来模拟其产生。所有分析物在皮肤组织中的横向分布都很少，注射后2小时其水平显著降低（> 95%）。然而，二十二碳六烯酸衍生物在生物学上比源自花生四烯酸或二十碳五烯酸的SPM更稳定。
