Thiostrepton-Nanomedicine, a TLR9 Inhibitor, Attenuates Sepsis-Induced Inflammation in Mice.
Thiostrepton-Nanomedicine, a TLR9 Inhibitor, Attenuates Sepsis-Induced Inflammation in Mice.
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DOI：
10.1155/2023/4035516
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发表时间：
2023
影响因子：
4.6
通讯作者：
Onyuksel, H.
中科院分区：
文献类型：
--
作者：
Esparza, K.;Oliveira, S. D.;Castellon, M.;Minshall, R. D.;Onyuksel, H.
脓毒症是由病原体和病原体相关分子模式（PAMP）感染和转位到宿主血流中引起的危及生命的临床病症。在脓毒症期间，免疫细胞上的Toll样受体（TLR）的激活触发促炎细胞因子的释放并过度刺激血管舒张介质如一氧化氮（NO）的产生。这些血管变化导致广泛的炎症、组织损伤、多器官衰竭，并且常常导致死亡。迫切需要新的治疗选择。为此，硫链丝菌素（TST）由于其作为抗生素和抗炎分子（TLR 7 -9抑制剂）的作用而成为脓毒症治疗的候选药物。文献中的报道表明，TLR 9抑制实质上抑制了过度的宿主炎症反应，并减弱了盲肠结扎穿孔（CLP）脓毒症小鼠模型中脓毒症诱导的死亡率。然而，据我们所知，TST从未被直接测试为用于管理脓毒症的治疗选择，可能是由于其低水溶性和药物递送问题。这些事实促使我们测试的中心假设，TST封装在磷脂空间稳定胶束（TST-SSM）可以开发成一种新的治疗败血症。因此，使用我们公开的包封疏水抗生素TST-SSM的方法，我们评估了TST-SSM纳米药物在多微生物败血症小鼠模型中的体内功效。我们发现TST-SSM通过减少血液和腹腔灌洗液中的细菌负荷，使CLP诱导的脓毒症小鼠的中位生存期从31小时增加到44小时。此外，促炎细胞因子（白细胞介素6和肿瘤坏死因子-α）和NO衍生物的血浆水平也降低，而肾和肝功能生物标志物肌酐和天冬氨酸转移酶显着改善。总之，我们确定TST-SSM纳米药物具有作为脓毒症管理治疗剂的显著潜力，主要是由于其抗炎和抗生素特性。
Sepsis is a life-threatening clinical condition caused by infection and transposition of pathogens and pathogen-associated molecular patterns (PAMPs) into the host bloodstream. During sepsis, activation of toll-like receptors (TLRs) on immune cells triggers the release of pro-inflammatory cytokines and overstimulates the production of vasodilatory mediators such as nitric oxide (NO). These vascular changes lead to widespread inflammation, tissue damage, multiple organ failure, and often death. New therapeutic options are urgently needed. To this end, thiostrepton (TST) has emerged as a candidate for sepsis treatment due to its action as an antibiotic and anti-inflammatory molecule (TLR7-9 inhibitor). Reports in the literature suggest that TLR9 inhibition substantially suppresses the excessive host inflammatory response and attenuates sepsis-induced mortality in the cecal ligation and puncture (CLP) murine model of sepsis. However, to the best of our knowledge, TST has never been directly tested as a therapeutic option for the management of sepsis, possibly due to its low water solubility and drug delivery issues. These facts prompted us to test the central hypothesis that TST encapsulated in phospholipid sterically stabilized micelles (TST-SSM) could be developed into a novel treatment for sepsis. Thus, using our published method of encapsulating the hydrophobic antibiotic TST-SSM, we evaluated the in vivo efficacy of TST-SSM nanomedicine in the murine model of polymicrobial sepsis. We found that TST-SSM increased the median survival of CLP-induced septic mice from 31 to 44 hr by reducing the bacterial burden in the blood and peritoneal lavage. Moreover, plasma levels of pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor-alpha) and NO derivatives were also reduced, whereas renal and hepatic function biomarkers creatinine and aspartate transferase were significantly improved. In conclusion, we identified that TST-SSM nanomedicine has significant potential as a therapeutic agent for sepsis management, primarily due to its anti-inflammatory and antibiotic properties.
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影响因子：
3.7
作者：
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通讯作者：
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Shi, Huashan
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