Circulating extracellular vesicles activate the pyroptosis pathway in the brain following ventilation-induced lung injury

Journal of Neuroinflammation

Shu Wu¹  Matthew R. Duncan¹  Rahul Kumar¹  Julia Meguro¹  Ronald Zambrano¹  Laura Chavez¹  Merline Benny¹  Karen C. Young¹  Vanessa Nunes de Paiva¹  Julia M. Eterno¹  Augusto F. Schmidt¹  Shaoyi Chen¹  W. Dalton Dietrich²  Roberta Brambilla² 

[1] Department of Pediatrics, University of Miami Miller School of Medicine, 1611 NW 12th Ave, 33136, Miami, FL, USA;The Miami Project To Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA;

关键词: Prematurity;    Mechanical ventilation;    Lung injury;    Brain injury;    Gasdermin D;    Pyroptosis;   

DOI  :  10.1186/s12974-021-02364-z

来源: Springer

【 摘 要 】

BackgroundMechanical 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.MethodsNeonatal 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.ResultsInjurious 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.ConclusionsThese findings suggest that circulating EVs can contribute to the brain injury and poor neurodevelopmental outcomes in preterm infants with VILI through activation of GSDMD.

【 授权许可】

CC BY