image: The increase of plasma PAI-1 levels after cardiac surgery with the cardiopulmonary bypass stimulates the release of eEVs into circulation to transport the enclosed FSTL1, which interact with TLR4 to activate JAK2/3/STAT3/IRF-1 signaling pathway, resulting in a cytokine/chemokine burst and excessive iNOS induction associated with a secondary lung inflammatory response, which contributes to ALI/ARDS. Targeting the JAK2/3/STAT3 signaling pathway is feasible for preventing eEV-induced ALI. view more
Credit: ©Science China Press
This study is led by professor Jingsong Ou (Division of Cardiac Surgery, Cardiovascular Diseases Institute,The First Affiliated Hospital, Sun Yat-sen University) and professor Jun Xu (Guangzhou Institute of Respiratory Health; The First Affiliated Hospital of Guangzhou Medical University). Acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), is a potentially life-threatening complication with a high incidence in patients undergoing cardiac surgery with cardiopulmonary bypass. The systemic inflammatory response caused by cardiopulmonary bypass surgery may be an important cause of postoperative ALI/ARDS. However, the undergoing mechanisms are unclear. Extracellular vesicles (EVs) are microvesicles secreted by cells during activation or apoptosis. It has been widely reported that EVs play an important role in the intercellular material transport and information exchange. However, it is unclear whether EVs are involved in the occurrence of ALI/ARDS after cardiac surgery with cardiopulmonary bypass.
Previously, Professor. Jingsong Ou research team revealed that the protein composition of EVs in patients with valvular heart disease is different before and after cardiac surgery with cardiopulmonary bypass. Postoperative extracellular vesicles (EVs) contain unique proteins mainly involved in coagulation. Plasminogen-activated inhibitor-1 (PAI-1) is an important component of blood coagulation. Previous studies have found that the increase of PAI-1 level in patients undergoing cardiac surgery with cardiopulmonary bypass is associated with an increased risk of acute respiratory distress syndrome (ARDS), suggesting that PAI-1 and EVs have an important relationship in the occurrence of ARDS after cardiac surgery with cardiopulmonary bypass. Meanwhile, Professor Jun Xu research team previously found that the key target sites of the signaling pathway mainly involved in innate immune inflammatory response are not only related to virus mediated ALI, but may also be important targets for EVs related ALI.
Using an impressive array of experiments, including patient samples, mouse models, micro CT scanning, and protein biochemistry in the present study, the Prof. Ou and Prof. Xu research teams found that the levels of plasma PAI-1 and endothelial cell-derived EVs (eEVs) significantly increase after cardiac surgery with cardiopulmonary bypass.The increase of plasma PAI-1 is positively correlated with the increase of eEVs. The increase of levels of plasma PAI-1 and eEVs is also positively correlated with the occurrence of postoperative ARDS. PAI-1 can stimulate vascular endothelial cells to produce follistatin-like protein 1 (FSTL1)-enriched eEVs. The eEVs can transport the FSTL1 to pulmonary vascular endothelial cells, which bind to the receptor toll like receptor 4 (TLR4) that participates in the innate immune inflammatory response on the surface of endothelial cells, activating the TLR4 to stimulate the downstream signal cascade Janus kinase 2/3 (JAK2/3) - signal transducer and activator of transcription 3 (STAT3) - interferon regulatory factor 1 (IRF-1) response, and form a positive feedback loop,causing cytokine/chemokine outbreaks and overexpression of inducible nitric oxide synthase (iNOS) to induce oxidative stress, ultimately leading to secondary pulmonary inflammatory response,resulting in ALI/ARDS.
More exciting findings are that the JAK2/3 inhibitors AG490, which is available in the clinic currently, or the STAT3 inhibitors S3I-201 can reduce the occurrence of eEVs-induced ALI/ARDS. The ALI/ARDS induced by eEVs can be inhibited in TLR4-/- and iNOS-/- mice. Deletion of FSTL1 from eEVs can also alleviate the occurrence of ALI/ARDS induced by eEVs.
This study elucidates a novel molecular mechanism for the occurrence of ALI/ARDS after cardiac surgery with cardiopulmonary bypass, and provides new therapeutic targets and medicines for ALI/ARDS after cardiac surgery with cardiopulmonary bypass.
See the article:
Endothelial extracellular vesicles induce acute lung injury via follistatin-like protein 1
Journal
Science China Life Sciences