内皮衍生微粒激活Jak/Stat信号通路损伤血管内皮诱导急性肺损伤

Acute lung injury(ALI) is a common complication with high mortality after cardiothoracic surgery. We have demonstrated that endothelial-derived microparticles (EMP) increased in heart diseases and could induce ALI. However, the mechanisms by which EMP induced ALI remain unclear. Previously, studies have found that janus kinase/signal transducers and activators of transcription (Jak/Stat) signaling pathway played an important role in ALI. Preliminary data showed that EMP could activate Jak/stat signaling pathway and upregulate its downstream factors including interferon-inducible protein 10, interferon regulatory factor 1, inducible nitric oxide synthase (iNOS) and interleukin-6 expression. Therefore, we hypothesize that EMP induce ALI by impairing vascular endothelium through Jak/Stat signaling pathway. In this study, endothelial cells, C57BL6 mice, TLR4-/-mice and iNOS-/-mice will be treated with EMP, and the changes of cytokines, immune cells, signaling pathways and histology will be measured. The aim of this study is to obtain the reliable evidence that EMP induce ALI by impairing vascular endothelium through Jak/Stat signaling pathway and illustrate the novel mechanisms by which EMP induce ALI. Findings from this study will provide scientific evidence for preventing and treating ALI by targeting EMP/Jak/Stat signaling pathway in the future.

急性肺损伤(ALI)是心胸外科术后常见并发症，死亡率高。我们已证明心脏疾病会导致内皮衍生微粒（EMP）升高和EMP可诱发ALI，但EMP诱发ALI的机制未明。既往研究发现Jak/Stat信号通路在ALI中起重要作用，初步实验显示EMP可激活血管内皮Jak/Stat信号通路和上调与之相关的干扰素诱导蛋白10、干扰素调节因子1、诱导一氧化氮合酶(iNOS)和白细胞介素6等物质。因此，我们提出EMP可能通过激活Jak/Stat信号通路损伤血管内皮诱导ALI。本项目通过EMP处理内皮细胞、正常小鼠、iNOS-/-小鼠、TOLL样受体缺乏小鼠，观察Jak/Stat相关的细胞因子、免疫细胞、信号通路和组织学的改变。旨在获得EMP通过激活Jak/Stat信号通路损伤血管内皮诱导ALI的可靠依据，阐明EMP导致ALI的新机制，为将来以EMP/Jak/Stat信号通路作为新靶标防治ALI提供科学依据。

急性肺损伤(ALI)是心胸外科术后常见并发症，死亡率高。我们已证明心脏疾病会导致内皮衍生微粒（EMP）升高和EMP可诱发ALI，但EMP诱发ALI的机制未明。我们既往研究发现Janus激酶/信号转导子和转录激活子(JAK/STAT)信号通路在ALI中起重要作用，本项目通过EMP处理内皮细胞、正常小鼠、诱导型一氧化氮合成酶缺乏（iNOS-/-）小鼠、TOLL样受体缺乏小鼠，观察Jak/Stat相关的细胞因子、免疫细胞、信号通路和组织学的改变。发现血浆纤溶酶原激活抑制剂-1(PAI-1)刺激产生的EMP被血管内皮细胞捕获，由EMP转移的卵泡抑素相关蛋白1（FSTL1）被TLR4识别，激活JAK/STAT-干扰素调节因子1（IRF-1）信号通路，诱导过量的iNOS和升高的细胞因子/趋化因子导致肺部炎症损伤和氧合功能障碍。给予JAK（AG490）或STAT（S3I-201）靶向制剂可阻断TLR4信号传导可以减少体外和体内EMP暴露后的炎症反应和过度氧化应激。在TLR4-/-小鼠身上可以得到类似的结果。在iNOS-/-小鼠中氧化应激损伤也减轻，但血浆趋化因子和肺免疫细胞浸润水平仍然升高。因此，EMP释放可以转移FSTL1，激发TLR4介导的免疫炎症信号导致ALI。JAK/STAT靶向药物对EMP相关ALI有预防和/或治疗作用。本项目获得EMP通过激活JAK/STAT信号通路损伤血管内皮诱导ALI的可靠依据，阐明EMP导致ALI的新机制，为将来以EMP/JAT/STAT信号通路作为新靶标防治ALI提供科学依据。