Circulating extracellular vesicles activate the pyroptosis pathway in the brain following ventilation-induced lung injury.
Circulating extracellular vesicles activate the pyroptosis pathway in the brain following ventilation-induced lung injury.
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DOI：
10.1186/s12974-021-02364-z
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发表时间：
2021-12-29
影响因子：
9.3
通讯作者：
Schmidt AF
中科院分区：
文献类型：
--
作者：
Chavez L;Meguro J;Chen S;de Paiva VN;Zambrano R;Eterno JM;Kumar R;Duncan MR;Benny M;Young KC;Dietrich WD;Brambilla R;Wu S;Schmidt AF
早产儿机械通气可导致肺损伤，并与不良的神经发育结局相关。然而，机械通气诱导的肺损伤（VILI）和脑损伤之间的联系还没有得到很好的定义。由于已知循环细胞外囊泡（EV）通过转移它们的货物连接远端器官，我们假设EV介导与VILI相关的炎性脑损伤。新生大鼠在出生后第7天以低（10 mL/kg）或高（25 mL/kg）潮气量机械通气1 h，然后恢复2周。从这些大鼠的血浆中分离外泌体并过继转移到正常新生大鼠中。我们通过蛋白质印迹和组织学评估了机械通气或外泌体转移对脑炎症和焦亡途径激活的影响。损伤性机械通气诱导了相似的炎症和焦亡标志物，如肺和脑中IL-1β增加和活化的caspase-1/gasdermin D（GSDMD），此外还诱导了脑中的小胶质细胞活化和细胞死亡。分离的EV富含外泌体标志物CD 9和CD 81，表明外泌体富集。从患有VILI的新生大鼠中分离的EV增加了caspase-1，但没有GSDMD。这些EV的连续转移导致神经炎症，伴随小胶质细胞活化以及脑中半胱天冬酶-1和GSDMD的活化，与在机械通气的新生大鼠中观察到的相似。这些发现表明，循环EV可通过激活GSDMD导致VILI早产儿的脑损伤和不良神经发育结局。在线版本包含补充材料，可通过10.1186/s12974-021-02364-z获得。
Mechanical ventilation of preterm newborns causes lung injury and is associated with poor neurodevelopmental outcomes. However, the mechanistic links between ventilation-induced lung injury (VILI) and brain injury is not well defined. Since circulating extracellular vesicles (EVs) are known to link distant organs by transferring their cargos, we hypothesized that EVs mediate inflammatory brain injury associated with VILI. Neonatal rats were mechanically ventilated with low (10 mL/kg) or high (25 mL/kg) tidal volume for 1 h on post-natal day 7 followed by recovery for 2 weeks. Exosomes were isolated from the plasma of these rats and adoptively transferred into normal newborn rats. We assessed the effect of mechanical ventilation or exosome transfer on brain inflammation and activation of the pyroptosis pathway by western blot and histology. Injurious mechanical ventilation induced similar markers of inflammation and pyroptosis, such as increased IL-1β and activated caspase-1/gasdermin D (GSDMD) in both lung and brain, in addition to inducing microglial activation and cell death in the brain. Isolated EVs were enriched for the exosomal markers CD9 and CD81, suggesting enrichment for exosomes. EVs isolated from neonatal rats with VILI had increased caspase-1 but not GSDMD. Adoptive transfer of these EVs led to neuroinflammation with microglial activation and activation of caspase-1 and GSDMD in the brain similar to that observed in neonatal rats that were mechanically ventilated. These findings suggest that circulating EVs can contribute to the brain injury and poor neurodevelopmental outcomes in preterm infants with VILI through activation of GSDMD. The online version contains supplementary material available at 10.1186/s12974-021-02364-z.
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影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
DOI：
10.1136/archdischild-2017-313864
发表时间：
2019-01-01
影响因子：
4.4
作者：
Mian, Qaasim;Cheung, Po-Yin;Schmolzer, Georg M.
通讯作者：
Schmolzer, Georg M.
加油动物：凋亡的效应因子。
影响因子：
19
作者：
Kovacs SB;Miao EA
通讯作者：
Miao EA
影响因子：
3.7
作者：
Polglase GR;Miller SL;Barton SK;Baburamani AA;Wong FY;Aridas JD;Gill AW;Moss TJ;Tolcos M;Kluckow M;Hooper SB
通讯作者：
Hooper SB
影响因子：
5.5
作者：
Barton, Samantha K.;McDougall, Annie R. A.;Tolcos, Mary
通讯作者：
Tolcos, Mary