Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.
Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.
复制标题
GW4869用GW4869的外泌体产生封锁会抑制败血症引起的炎症和心脏功能障碍。
DOI：
10.1016/j.bbadis.2015.08.010
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Fan GC
中科院分区：
文献类型：
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作者：
Essandoh K;Yang L;Wang X;Huang W;Qin D;Hao J;Wang Y;Zingarelli B;Peng T;Fan GC
脓毒症是一种感染引起的严重炎症性疾病，可导致多器官功能衰竭。在受影响的器官中，心肌抑制被认为是脓毒性死亡的主要原因。虽然已经确定大量的循环促炎细胞因子是脓毒症中触发心脏功能障碍的罪魁祸首，但其潜在机制仍不清楚。此外，最近的研究表明，从细菌感染的巨噬细胞释放的外泌体是促炎性的。因此，我们在这项研究中检查了阻断外泌体的产生是否会对脓毒症诱导的炎症反应和心脏功能障碍具有保护作用。为此，我们用GW 4869预处理RAW 264.7巨噬细胞，GW 4869是一种外泌体生物发生/释放的抑制剂，然后进行内毒素（LPS）攻击。在体内，我们用GW 4869注射野生型（WT）小鼠1小时，然后进行内毒素处理或盲肠结扎/穿刺（CLP）手术。我们观察到用GW 4869预处理显著损害了RAW 264.7巨噬细胞中外来体和促炎细胞因子（TNF-α、IL-1β、IL-6）的释放。在LPS处理或CLP手术后12小时，用GW 4869预处理的WT小鼠在血清中显示出比对照PBS注射小鼠更低量的外泌体和促炎细胞因子。因此，GW 4869治疗减轻了脓毒症诱导的心脏炎症，减轻了心肌抑制并延长了存活期。总之，我们的研究结果表明，在脓毒症中阻断外泌体的产生抑制脓毒症触发的炎症反应，从而改善心脏功能和存活率。
Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.