首页|Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1

Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1

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Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI),including acute respiratory distress syndrome(ARDS),in patients after cardiac surgery.We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles(eEVs)with components of coagulation and acute inflammatory responses.However,the mechanism underlying the onset of ALI owing to the release of eEVs after cardiopulmonary bypass,remains unclear.Plasma plasminogen-activated inhibitor-1(PAI-1)and eEV levels were measured in patients with cardiopulmonary bypass.Endothelial cells and mice(C57BL/6,Toll-like receptor 4 knockout(TLR4-/-)and inducible nitric oxide synthase knockout(iNOS-/-))were challenged with eEVs isolated from PAI-1-stimulated endothelial cells.Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass.Plasma PAI-1 eleva-tion was positively correlated with the increase in eEVs.The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS.The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade iden-tified as the Janus kinase 2/3(JAK2/3)-signal transducer and activator of transcription 3(STAT3)-interferon regulatory factor 1(IRF-1)pathway,along with iNOS induction,and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice,ultimately contributing to ALI.ALI could be attenuated by JAK2/3 or STAT3 inhibitors(AG490 or S3I-201,respectively),and was relieved in TLR4-/-and iNOS-/-mice.eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1(FSTL1),and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS.Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs,which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop,leading to ALI/ARDS after cardiac surgery.Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.

cell-derived extracellular vesiclesacute lung injuryacute respiratory distress syndromecardiopulmonary bypassfollistatin-like protein 1

Hao-Xiang Yuan、Ya-Ting Chen、Yu-Quan Li、Yan-Sheng Wang、Zhi-Jun Ou、Yan Li、Jian-Jun Gao、Meng-Jie Deng、Yuan-Kai Song、Li Fu、Hong-Bo Ci、Feng-Jun Chang、Yang Cao、Yu-Peng Jian、Bi-Ang Kang、Zhi-Wei Mo、Da-Sheng Ning、Yue-Ming Peng、Ze-Long Liu、Xiao-Jun Liu、Ying-Qi Xu、Jun Xu、Jing-Song Ou

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Division of Cardiac Surgery,Cardiovascular Diseases Institute,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China

National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases,NHC Key Laboratory of Assisted Circulation(Sun Yat-sen University),Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases,Guangzhou 510080,China

State Key Laboratory of Respiratory Disease,Guangzhou 510120,China

Guangzhou Institute of Respiratory Health,Guangzhou 510120,China

The First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China

Division of Hypertension and Vascular Diseases,Cardiovascular Diseases Institute,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China

Guangdong Provincial Key Laboratory of Brain Function and Disease,Guangzhou 510080

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国家重点研发计划国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金National Natural Science Foundation of China Distinguished Young Scholar Grant"973 Project"from the Ministry of Science and Technology of ChinaGuangdong Basic and Applied Basic Research FoundationScience and Technology Planning Project of Guangzhou,ChinaChangjiang Scholars Program from the Ministry of Education of ChinaSun Yatsen University Clinical Research 5010 ProgramProgram of National Key Clinical Specialties

2021YFA080510081830013817702418197036382000362922682028117027181370370814905318167039281600382813250012009CB5221042019B1515120092202103000016

2024

10.1007/s11427-022-2328-x

中国科学:生命科学(英文版)
中国科学院

中国科学:生命科学(英文版)

CSTPCD
影响因子：0.806
ISSN：1674-7305
年,卷(期)：2024.67(3)
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