血小板微粒调节炎性反应：机制与临床意义解析

Leukocyte activation is one of the main reasons of organ injury during Systemic Inflammatory Response Syndrome (SIRS). In the pilot studies we found that platelet mircroparticles (PMP) are produced by the activated platelet during SIRS. These PMPs adhere to or embedded in the cell membrane of leukocyte via the adhesion molecules on their membrane. The apoptosis signal was also observed in PMP-leukocyte. Because caspase 9 is activated during platelet activation, and this activated caspase may be passed to PMP. Therefore, we hypothesized that PMP may regulate the inflammatory response by inducing leukocyte apoptosis process. In this project, cardiopulmonary bypass-induced SIRS model will be applied to explore the variations of PMP and PMP-leukocyte, and their correlation with organ function and prognosis of patients to resolve its clinical significance. PMP-leukocyte apoptosis will also be observed to speculate the mechanism of PMP on the activated leukocyte. To identify this potential mechanism, caspase 9 in PMP will be blocked, and these PMP will be cultured with leukocyte, or injected to rat SIRS model induced by extracorporeal circulation. Then leukocyte apoptosis, degranulation, adhesion to vascular endothelial cell will be observed in in vitro study, while inflammatory response and organ injury will be determined in in vivo study. Therefore, our project will not only be provided an ideal index of clinical outcomes, but also allow us to profound understand the balance between the inflammatory response and anti-inflammatory response, which may provided a theoretical and experimental basis for the development of specific drugs or treatments for SIRS.

白细胞活化是全身炎性反应综合征（SIRS）导致器官损伤的主要原因之一。我们的前期研究发现，SIRS能够导致大量血小板微粒（PMP）形成，PMP借助于表面粘附分子，以粘附或嵌入细胞膜的形式活跃的出现在白细胞表面，随之融合白细胞出现凋亡。由于PMP形成中能激活凋亡蛋白caspase-9，因此PMP可能同时携带凋亡信息。这些证据提示PMP可能通过诱导白细胞凋亡而调节炎性反应。为此本研究仍以体外循环诱导的SIRS为模型，探讨PMP、PMP-白细胞的变化规律、PMP对白细胞凋亡的影响，并与患者预后进行相关性分析；使用细胞培养、大鼠体外循环模型，通过阻断caspase-9的激活，研究PMP诱导白细胞凋亡的机制，以及诱导凋亡对SIRS的抑制作用和对器官的保护作用。本课题不仅为临床提供一个良好的预后指标，而且为深刻理解机体的炎性/抗炎之间的平衡机制，从而开发特异性药物或治疗手段提供理论依据。

炎性反应几乎贯穿所有疾病过程，是导致器官组织损伤的的重要因素。我们的前期研究发现，血小板微粒（PMP）可能具有重要的炎性调节作用。经过4年的努力，我们顺利完成本课题并证实：（1）PMP可以嵌入、融合等方式与白细胞结合形成复合体，诱导白细胞发生凋亡而密切调节炎症反应；（2）PMP-白细胞复合物的数量与炎性反应相关疾病，特别是心脏瓣膜置换术后心血管事件的发生密切相关；（3）然而，如果PMP通过血小板-内皮细胞间粘附分子（CD31）作用于血管内皮细胞，则能够导致内细胞紧密连接的破坏，而加重炎症早期的血管渗漏反应；（4）体外循环手术中抑制血小板激活，可减少患者术后并发症发生率，改善患者预后。 . 可见，PMP通过多种机制调节炎性反应，并最终影响患者预后。本项目的研究结果不仅为炎性反应相关疾病提供一个良好的预后指标，也为深入了解机体的炎性/抗炎之间的平衡机制、炎性反应相关疾病的发病机制和临床个体化治疗提供新思路，为开发特异性药物或治疗手段提供理论和实验依据。