Sepsis is characterized by systemic inflammatory response syndrome (SIRS) accompanied with infection. Gram‐negative bacteria can evoke sepsis by activating the host immune system, such as the release of IL‐6 and TNF‐α, through their virulence factors. Outer membrane vesicles (OMVs), nanosized bilayered proteolipids derived from Gram‐negative bacteria, harbor various virulence factors and are shown to induce SIRS. Here, drugs are repositioned to alleviate SIRS caused by Gram‐negative bacterial OMVs. Using novel OMV‐based drug screening systems, a total of 178 commercially available drugs are primarily screened, and a total of 18 repositioned drug candidates are found to effectively block IL‐6 and TNF‐α production from OMV‐stimulated macrophages. After excluding the compounds which are previously known to intervene sepsis or which show cytotoxicity to macrophages, the compounds which show dose‐dependency in inhibiting the release of IL‐6 and TNF‐α by the OMV‐stimulated macrophages in vitro and which reduce OMV‐induced SIRS in vivo are selected. Salbutamol, a β2 adrenergic receptor agonist, is selected as a novel candidate to alleviate OMV‐induced SIRS. This study sheds light on using Gram‐negative bacterial OMVs in exploring novel candidate compounds to alleviate inflammatory diseases including sepsis.

中文翻译：

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药物重新定位以减轻革兰氏阴性细菌外膜囊泡引起的全身炎症反应综合征

败血症的特征在于伴随感染的全身性炎症反应综合征（SIRS）。革兰氏阴性细菌可通过其毒性因子激活宿主免疫系统（例如IL-6和TNF-α的释放）来诱发败血症。外膜囊泡（OMV）是源自革兰氏阴性细菌的纳米级双层蛋白脂，具有多种毒力因子，可诱导SIRS。在这里，将药物重新定位以减轻由革兰氏阴性细菌OMV引起的SIRS。使用新颖的基于OMV的药物筛选系统，主要筛选了178种市售药物，并且发现总共18种重新定位的候选药物可有效阻断OMV刺激的巨噬细胞产生IL-6和TNF-α。在排除先前已知可干预败血症或对巨噬细胞显示细胞毒性的化合物后，这些化合物在体外被OMV刺激的巨噬细胞抑制IL-6和TNF-α的释放表现出剂量依赖性，并降低OMV-选择诱导的体内SIRS。沙丁胺醇是一种β2肾上腺素能受体激动剂，被选为缓解OMV诱导的SIRS的新型候选药物。这项研究为使用革兰氏阴性细菌OMV探索新型候选化合物减轻包括败血症在内的炎性疾病提供了可能。被选为缓解OMV诱导的SIRS的新型候选药物。这项研究为使用革兰氏阴性细菌OMV探索新型候选化合物减轻包括败血症在内的炎性疾病提供了可能。被选为缓解OMV诱导的SIRS的新型候选药物。这项研究为使用革兰氏阴性细菌OMV探索新型候选化合物减轻包括败血症在内的炎性疾病提供了可能。