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Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
Anum Ali1, Ronald Zambrano1, Matthew R Duncan1
1Division of Neonatology and Batchelor Children's Research Institute, Department of Pediatrics, University of Miami Miller School of Medicine, P. O. Box 016960, Miami, FL, 33101, USA.
Insights
Hyperoxia causes lung injury in preterm infants, leading to brain damage via circulating extracellular vesicles (EVs). These EVs carry inflammatory cargo, linking lung and brain injury in bronchopulmonary dysplasia (BPD).
Area of Science:
- Neonatal medicine
- Cell biology
- Neuroscience
Background:
- Bronchopulmonary dysplasia (BPD) involves lung injury and impaired development in preterm infants, predicting poor neurodevelopmental outcomes.
- The precise mechanisms linking lung injury to brain injury in BPD remain unclear.
- Extracellular vesicles (EVs) mediate intercellular communication, potentially linking organ damage.
Purpose of the Study:
- To investigate if hyperoxia induces lung release of circulating EVs.
- To determine if these EVs contribute to lung and brain injury in a neonatal rat model.
- To explore the role of Gasdermin D (GSDMD) in hyperoxia-induced EV-mediated injury.
Main Methods:
- Neonatal rats were exposed to hyperoxia to model BPD.
- Plasma EVs were isolated and characterized for cargo (surfactant protein C, active GSDMD).
- EVs were adoptively transferred to assess their impact on recipient rats' lung and brain tissues, and on cultured cells (pulmonary vascular endothelial cells, neural stem cells).
Main Results:
- Hyperoxia increased plasma EV levels in rats.
- These EVs contained elevated surfactant protein C and active GSDMD (GSDMD-p30).
- Adoptive transfer of these EVs induced BPD hallmarks and brain inflammatory injury in recipients, and cell death in cultured cells.
Conclusions:
- Hyperoxia-activated circulating EVs mediate lung-to-brain crosstalk.
- These EVs contribute to brain injury and neurodevelopmental impairment in BPD.
- GSDMD-containing EVs represent a key mechanism linking lung injury to brain damage in BPD.
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.
