Brain-derived extracellular vesicles mediated coagulopathy, inflammation and apoptosis after sepsis

Abstract

The activation of coagulation, inflammation and other pathways is the basic response of the host to infection in sepsis, but this response also causes damage to the host. Brain-derived extracellular vesicles (BDEVs) have been reported to cause a hypercoagulable state that can rapidly develop into consumptive coagulopathy, which is consistent with the pathophysiological process of sepsis-induced coagulopathy. However, the role of BDEVs in sepsis-induced coagulopathy remains unclear. Materials and methods: Male Sprague-Dawley (SD) rats were used for sepsis modeling using cecal ligation puncture (CLP). Flow cytometry was used to measure the levels of circulating BDEVs. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of plasminogen activator inhibitor type 1 (PAI-1), thrombin-antithrombin (TAT), D-dimer, fibrinogen(Fib), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. Nanoparticle tracking analysis (NTA) and Transmission electron microscopy (TEM) were used to identify BDEVs. Western blot (WB) was used to determine the expression of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), bax, bcl-2 and cleaved caspase-3. Hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to detect tissue injury. Survival was monitored over the course of 168 h. Results: We found that a large number of BDEVs were released into the circulating blood in septic rats. Moreover, we observed that BDEVs injection activated the systemic coagulation reaction and induced lung, liver and kidney inflammation and apoptosis(P < .05). Compared with BDEVs from sham-operated rats, BDEVs from septic rats exacerbated this process(P < .05). Conclusions: This finding suggests that inhibiting BDEVs may yield therapeutic benefits in the treatment of sepsisinduced coagulopathy.

Unraveling the Multifaceted Roles of Extracellular Vesicles: Insights into Biology, Pharmacology, and Pharmaceutical Applications for Drug Delivery

“…It has been demonstrated that traumatic brain injury in mice caused a release of EVs from microglia, while injection of these EVs into a healthy mouse brain led to neuroinflammation [ 184 ]. Intrastriatal injection of brain-derived EVs has been reported to activate microglia and stimulate the release of pro-inflammatory mediators; therefore, EVs could act locally to exacerbate central inflammation after initial injury [ 185 ]. Of note, it has been demonstrated that after stroke [ 186 ] and TBI [ 187 , 188 ], an increased number of circulating EVs had the potential to induce systemic immune reaction [ 186 , 188 ], indicating EV-mediated brain–immune system communication.…”

The Pathophysiology of Sepsis-Associated AKI

“…This increase is not consistent with the fact that ATF3 expression is repressed by miR-494, and urinary miR-494 was elevated during AKI (97,98); however, the finding that miRNAs contribute to the determination of extracellular vesicle release and intracellular retention (108) may be the key to clarifying the relationship between miR-494 and exosomal ATF3. Lin et al demonstrated the functional effect of brain-derived extracellular vesicles (mainly from neurons and astrocytes) on kidney tissue in sepsis; treatment with brain-derived extracellular vesicles exacerbated sepsis-induced injury and apoptosis in the kidney of rats (109). Moreover, Seibold et al suggested that extracellular vesicles secreted on thorax trauma are strongly associated with sepsis and biochemical markers of AKI (110).…”

Extracellular Vesicles as Regulators of Immune Function in Traumatic Injuries and Sepsis

“…The primary sources of plasma EVs released during sepsis are platelets and circulating immune cells, such as macrophages, dendritic cells, neutrophilic granulocytes, and natural killer cells ( 54 , 55 ). However, recent studies have found that EVs released from the astrocytes and perhaps neurons could possibly contribute to sepsis-related complications ( 56 ). Lin et al measured expression of glial fibrillary acidic protein (GFAP) and neuron-specific enolase in plasma EVs.…”