Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats

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 i...

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Autores principales:	Anum Ali, Ronald Zambrano, Matthew R. Duncan, Shaoyi Chen, Shihua Luo, Huijun Yuan, Pingping Chen, Merline Benny, Augusto Schmidt, Karen Young, Nadine Kerr, Juan Pablo de Rivero Vaccari, Robert W. Keane, W. Dalton Dietrich, Shu Wu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/15155bae7ccb4cd9aba80857a69a7304
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spelling	oai:doaj.org-article:15155bae7ccb4cd9aba80857a69a73042021-12-02T18:27:47ZHyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats10.1038/s41598-021-87706-w2045-2322https://doaj.org/article/15155bae7ccb4cd9aba80857a69a73042021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87706-whttps://doaj.org/toc/2045-2322Abstract 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.Anum AliRonald ZambranoMatthew R. DuncanShaoyi ChenShihua LuoHuijun YuanPingping ChenMerline BennyAugusto SchmidtKaren YoungNadine KerrJuan Pablo de Rivero VaccariRobert W. KeaneW. Dalton DietrichShu WuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anum Ali Ronald Zambrano Matthew R. Duncan Shaoyi Chen Shihua Luo Huijun Yuan Pingping Chen Merline Benny Augusto Schmidt Karen Young Nadine Kerr Juan Pablo de Rivero Vaccari Robert W. Keane W. Dalton Dietrich Shu Wu Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
description	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.
format	article
author	Anum Ali Ronald Zambrano Matthew R. Duncan Shaoyi Chen Shihua Luo Huijun Yuan Pingping Chen Merline Benny Augusto Schmidt Karen Young Nadine Kerr Juan Pablo de Rivero Vaccari Robert W. Keane W. Dalton Dietrich Shu Wu
author_facet	Anum Ali Ronald Zambrano Matthew R. Duncan Shaoyi Chen Shihua Luo Huijun Yuan Pingping Chen Merline Benny Augusto Schmidt Karen Young Nadine Kerr Juan Pablo de Rivero Vaccari Robert W. Keane W. Dalton Dietrich Shu Wu
author_sort	Anum Ali
title	Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
title_short	Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
title_full	Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
title_fullStr	Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
title_full_unstemmed	Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
title_sort	hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/15155bae7ccb4cd9aba80857a69a7304
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Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats

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