摘要
背景:关于七种组蛋白去乙酰化酶III类亚型Sirtuin(SIRT)1-7早有报道。最近,我们证明了SIRT1的抑制剂EX-527能够降低盲肠结扎穿孔感染性休克模型小鼠死亡率。本研究的目的是确定SIRT2选择性抑制AGK2是否能够会减少动物死亡和减轻脓毒症模型炎症反应。 方法:实验I:在二甲基亚砜(DMSO)环境中给C57BL/6J小鼠腹腔注射AGK2(82 mg/kg)或只在DMSO中不给药喂养,2 h后进行盲肠结扎穿孔,然后对其240小时内的生存状况进行监测。实验II:小鼠与实验一做同样处理,一组为(i)DMSO组,另一组为(ii)AGK2组,并与假手术组小鼠(进行手术,但不作任何治疗处理)进行对照。24和48小时后对腹膜液和外周血中细胞因子产生的进行检查。通过血栓弹力图(TEG)对48小时后的血液样本进行凝血能力评估。骨髓形态学的改变由采用苏木精-伊红(H&E)染色的长骨(股骨和胫骨)进行评估。盲人病理学家对骨髓萎缩进行量化。实验三:在细胞受到脂多糖刺激并分别使用或不用AGK2进行治疗后对体外培养的正常原发性脾细胞上清液中细胞因子进行测定。 结果:AGK2显著降低死亡率和降低细胞因子水平(TNF-α::298.3 ± 24.6/26.8 ± 2.8pg/ml,p = 0.0034;IL-6:633.4 ± 82.8/232.6 ± 133.0 pg/ml,p = 0.0344)以及减少腹腔液 (IL-6: 704.8 ± 67.7/391.4 ± 98.5 pg/ml, p=0.033)。同时,AGK2抑制了体外培养小鼠脾细胞中TNF-α和IL-6的产生 (TNF-α: 68.1 ± 6.4 / 23.9 ± 2.8 pg/ml, p = 0.0009; IL-6: 73.1 ± 4.2 / 49.6 ± 3.0 pg/ml; p = 0.0051)。TEG数据显示,经过盲肠结扎穿孔的小鼠能够延长纤维蛋白形成和纤维蛋白交联时间、使凝块形成减慢、降低血小板功能和凝血的刚性。AGK2治疗与纤维蛋白交联和血栓形成时间的改善有关,其对血栓形成参数或血小板功能并没有太大的影响。此外,AGK2能够明显减轻骨髓萎缩症状(58.3 ± 6.5/30 ± 8.2%, P = 0.0262)。 结论:SIRT2选择性抑制剂能显着提高生存率;减轻脓毒症“细胞因子风暴”、凝血功能障碍和脓毒性休克小鼠骨髓萎缩。
关键词: 骨髓萎缩,小鼠模型,SIRT2抑制剂,脓毒性休克,存活率
Current Molecular Medicine
Title:Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model
Volume: 15 Issue: 7
Author(s): T. Zhao, H.B. Alam, B. Liu, R.T. Bronson, V.C. Nikolian, E. Wu, W. Chong and Y. Li
Affiliation:
关键词: 骨髓萎缩,小鼠模型,SIRT2抑制剂,脓毒性休克,存活率
摘要: Background: Seven isoforms of histone deacetylase Class III have been reported - Sirtuin (SIRT) 1-7. We recently demonstrated that EX-527, an inhibitor of SIRT1, reduces mortality in a mouse model of lethal-cecal-ligationand- puncture (CLP)-induced septic shock. Our present study was aimed at determining whether selective inhibition of SIRT2, with AGK2, would decrease animal death and attenuate the inflammatory response in a septic model.
Methods: Experiment I: C57BL/6J mice were intraperitoneally given either AGK2 (82 mg/kg) in dimethyl sulfoxide (DMSO) or DMSO alone, and 2 h later subjected to CLP. Survival was monitored for 240 hours. Experiment II: mice treated the same way as Experiment I, were grouped into (i) DMSO vehicle, and (ii) AGK2, with sham mice (operating but without any treatment) serving as controls. Peritoneal fluid and peripheral blood were examined at 24 and 48 hours for cytokine production. Samples of blood at 48 h were also allocated to assess coagulability using Thrombelastography (TEG). Morphological changes of bone marrow were evaluated from long bones (femurs and tibias) with hematoxylin and eosin (H&E) staining. Bone marrow atrophy was quantified by a blinded pathologist. Experiment III: cytokines in supernatant of the cultured normal primary splenocytes were measured after the cells were stimulated by lipopolysaccharide and treated with or without AGK2 (10 µM) for 6 hours.
Results: AGK2 significantly reduced mortality and decreased levels of cytokines in blood (TNF-α: 298.3±24.6 vs 26.8±2.8 pg/ml, p=0.0034; IL-6: 633.4±82.8 vs 232.6±133.0 pg/ml, p=0.0344) and peritoneal fluid (IL-6: 704.8±67.7 vs 391.4±98.5 pg/ml, p=0.033) compared to vehicle control. Also, AGK2 suppressed the TNF-α and IL-6 production in the cultured splenocytes (TNF-α: 68.1±6.4 vs 23.9±2.8 pg/ml, p=0.0009; IL-6: 73.1±4.2 vs 49.6±3.0 pg/ml; p=0.0051). The TEG data showed that the mice subjected to CLP displayed prolonged fibrin formation and fibrin cross-linkage time, slower clot formation, decreased platelet function, and clot rigidity. AGK2 treatment was associated with dramatic improvements in fibrin cross-linkage and clot formation times, without a significant impact on the clot initiation parameters or platelet function. Additionally, AGK2 significantly attenuated the bone marrow atrophy (58.3±6.5 vs 30.0±8.2%, p=0.0262).
Conclusion: Selective inhibition of SIRT2 significantly improves survival, and attenuates sepsis-associated “cytokine storm”, coagulopathy, and bone marrow atrophy in a mouse model of lethal septic shock.
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Cite this article as:
T. Zhao, H.B. Alam, B. Liu, R.T. Bronson, V.C. Nikolian, E. Wu, W. Chong and Y. Li , Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model, Current Molecular Medicine 2015; 15 (7) . https://dx.doi.org/10.2174/156652401507150903185852
DOI https://dx.doi.org/10.2174/156652401507150903185852 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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