Simvastatin and a Plant Galactolipid Protect Animals from Septic Shock by Regulating Oxylipin Mediator Dynamics through the MAPK-cPLA2 Signaling Pathway
Simvastatin and a Plant Galactolipid Protect Animals from Septic Shock by Regulating Oxylipin Mediator Dynamics through the MAPK-cPLA2 Signaling Pathway
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DOI：
10.2119/molmed.2015.00082
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发表时间：
2015-01-01
影响因子：
5.7
通讯作者：
Shyur, Lie-Fen
中科院分区：
文献类型：
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作者：
Apaya, Maria Karmella;Lin, Chih-Yu;Shyur, Lie-Fen
尽管经过数十年的研究，脓毒症仍然是一个主要的医学问题。识别重要的炎症级联和关键分子介质对于制定干预和预防策略至关重要。在本研究中，我们进行了比较氧脂代谢组学研究，以全面了解脓毒症初始高炎症阶段的脂质介质动态，并同时证明辛伐他汀和植物半乳糖脂、1,2-二-O-α-亚麻酰-3-O-β-吡喃半乳糖基-sn-甘油（dLGG）在氧脂代谢组稳态调节中的功效。脂多糖 (LPS) 诱导的脓毒症 C57BL/6J 小鼠模型。 LPS 增加亚油酸促炎代谢物的全身和器官水平，包括白细胞毒素二醇（9-,10-DHOME、12-,13-DHOME）和十八碳二烯酸（9-HODE 和 13-HODE）以及花生四烯酸衍生的前列腺素、PGE2 和羟基二十碳四烯酸（8-、12-和 15-HETE）。用任一化合物治疗均可降低促炎代谢物的水平，并升高促分解脂氧素 A4、5(6)-EET、11(12)-EET 和 15-脱氧-PGJ2。 dLGG 和辛伐他汀改善了 LPS 诱导的丝裂原激活蛋白激酶 (MAPK) 依赖性 cPLA2、环氧合酶 2、脂氧合酶、细胞色素 P450 和/或环氧化物水解酶激活的作用，降低了全身 TNF-α 和 IL-6 水平以及转氨酶活性，并减少了炎症性白细胞和巨噬细胞的器官特异性浸润，以及败血性休克诱导的多器官损坏。此外，dLGG 和辛伐他汀均可提高盲肠结扎穿刺 (CLP) 脓毒症模型的存活率。这项研究为氧脂素在脓毒症发病机制中的作用提供了新的见解，并强调了辛伐他汀和 dLGG 在脓毒症治疗和预防中的潜力。
Sepsis remains a major medical issue despite decades of research. Identification of important inflammatory cascades and key molecular mediators are crucial for developing intervention and prevention strategies. In this study, we conducted a comparative oxylipin metabolomics study to gain a comprehensive picture of lipid mediator dynamics during the initial hyperinflammatory phase of sepsis, and demonstrated, in parallel, the efficacy of simvastatin and plant galactolipid, 1,2-di-O-alpha-linolenoyl-3-O-beta-galactopyranosyl-sn-glycerol (dLGG) in the homeostatic regulation of the oxylipin metabolome using a lipopolysaccharide (LPS)-induced sepsis C57BL/6J mouse model. LPS increased the systemic and organ levels of proinflammatory metabolites of linoleic acid including leukotoxin diols (9-,10-DHOME, 12-,13-DHOME) and octadecadienoic acids (9-HODE and 13-HODE) and arachidonic acid-derived prostanoid, PGE2, and hydroxyeicosatetraenoic acids (8-, 12- and 15-HETE). Treatment with either compound decreased the levels of proinflammatory metabolites and elevated proresolution lipoxin A4, 5(6)-EET, 11(12)-EET and 15-deoxy-PGJ2. dLGG and simvastatin ameliorated the effects of LPS-induced mitogen-activated protein kinase (MAPK)-dependent activation of cPLA2, cyclooxygenase-2, lipoxygenase, cytochrome P450 and/or epoxide hydrolase lowered systemic TNF-alpha and IL-6 levels and aminotransferase activities and decreased organ-specific infiltration of inflammatory leukocytes and macrophages, and septic shock -induced multiple organ damage. Furthermore, both dLGG and simvastatin increased the survival rates in the cecal ligation and puncture (CLP) sepsis model. This study provides new insights into the role of oxylipins in sepsis pathogenesis and highlights the potential of simvastatin and dLGG in sepsis therapy and prevention.