Abstract
Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants.
Highlights
Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants
Nanosight tracking assay revealed that both RA-Extracellular vesicles (EVs) (Fig. 1A) and O2-EVs (Fig. 1B) contained nanoparticles that were primarily of a 30–150 nm exosome size, with both peaking at 100–150 nm in diameter, but the nanoparticle concentrations of O 2-EVs were 2.4fold higher than RA-EVs (Fig. 1C, P < 0.05)
Western blot analysis confirmed that O 2-EVs contained twofold increased levels of SPC (Fig. 1G, H, O2-EVs 438.7 ± 80.5 vs. RA-EVs 200.3 ± 101.8, P < 0.01) and activated Gasdermin D (GSDMD)-p30 compared to RA-EVs, which contained primarily inactive GSDMD-p53 (Fig. 1G, I, O2-EVs 0.90 ± 0.23 vs. RAEVs 0.45 ± 0.24, P < 0.01) (Supplemental Fig. 1G)
Summary
Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air These EVs had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. Hyperoxiaexposed cultured AEC-like cells released EVs that contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants. In preterm infants with severe BPD, increased numbers of EVs were detected in their tracheal aspirates, and interestingly, the majority of these EVs were found to be of epithelial o rigin[13] These data suggest that lung epithelial cells can release bioactive EVs into airspace fluid upon inflammatory injury. GSDMD-p30 has recently been detected in serum exosomal microparticles from adult patients with sepsis and acute lung injury[23], but it is presently unknown if exosomal GSDMD plays a mechanistic role in the pathogenesis of BPD or brain injury in preterm infants
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