TSP1-血小板源性微粒介导颅脑损伤后肠道细菌移位所致肺部感染的作用机制研究

Intestinal mucosal barrier dysfunction often occurs after traumatic brain injury, and pulmonary infection is the most common complication of traumatic brain injury. Previous studies have shown that most of the pathogenic bacteria of the pulmonary infection after brain injury are intestinal symbiotic bacteria. This suggests that the intestinal mucosal barrier dysfunction after traumatic brain injury may lead to intestinal bacterial translocation and pulmonary infection. However, the specific mechanism is still unclear. Activation of the coagulation pathway after traumatic brain injury can lead to the massive formation and release of TSP1 and TSP1-platelet derived microparticles into the blood. Previous studies have shown that the release of platelet-derived microparticles into the blood can be targeted to other organs and TSP1 can mediate intestinal inflammation. Therefore, we will take these as the key points to clarify the release of TSP1-platelet derived microparticles from brain after traumatic brain injury, to analyze the effect of TSP1-platelet derived microparticles mediated immune dysfunction on the intestinal mucosal barrier and to further explore the correlation between intestinal bacterial translocation after intestinal barrier dysfunction and pulmonary infection after traumatic brain injury by the 16S rRNA gene sequencing and bioinformatics analysis. We proposed the hypothesis that the TSP1-platelet-derived microparticles can lead to intestinal bacterial translocation and further pulmonary infection after traumatic brain injury, in order to provide experimental basis for prevention and treatment of intestinal and pulmonary complications after traumatic brain injury.

颅脑创伤后常常出现肠粘膜屏障功能受损，肺部感染又是颅脑创伤最常见的并发症。以往研究显示脑损伤后肺部感染的致病菌大多为肠道共生菌。这提示颅脑损伤后肠粘膜屏障功能受损可能导致肠道细菌移位并发肺部感染，但具体机制仍不清楚。颅脑创伤后凝血途径的激活可以导致TSP1以及TSP1-血小板源性微粒的大量生成及释放入血。血小板源性微粒释放入血可以靶向作用于其他器官以及TSP1可以介导肠道炎症在以往研究中也有表明。为此，我们将以此为重点，希望通过本项目明确颅脑创伤后脑组织中TSP1-血小板源性微粒的释放，分析TSP1-血小板源性微粒释放介导的免疫紊乱对肠道粘膜屏障的影响，并通过16S rRNA基因扩增测序和生信学分析进一步探索肠道屏障受损后细菌移位与肺部感染的相关性，提出颅脑创伤后TSP1-血小板源性微粒的释放可以作用于肠粘膜导致肠道细菌移位后肺部感染的假说，为颅脑创伤后肠道与肺部并发症的防治提供实验基础。

颅脑创伤(TBI)后常常出现肠粘膜屏障功能受损，肺部感染又是颅脑创伤最常见的并发症。以往研究显示脑损伤后肺部感染的致病菌大多为肠道共生菌。这提示颅脑损伤后肠粘膜屏障功能受损可能导致肠道细菌移位并发肺部感染，但具体机制仍不清楚。为此，我们将以此为重点，希望通过本项目明确颅脑创伤介导的肠道菌群紊乱对肠道粘膜屏障的影响及具体机制，并通过16S rRNA基因扩增测序和生信学分析进一步探索肠道屏障受损后细菌移位与肺部感染的相关性，为颅脑创伤后肠道与肺部并发症的防治提供实验基础。通过本项目的研究，我们首先探索出TBI后肠道菌群和肺部菌群均存在明显失调。肠道细菌在TBI后可能转移到肺部，而Paneth细胞可能调节肠道微生物群的稳定性和转移。然后，我们还明确了TBI后损伤脑组织释放大量的HMGB1与潘氏细胞功能障碍、抗菌肽表达下降和肠道菌群失调存在密切相关性。通过培养小肠类器官和构建小鼠TBI模型证实TBI后损伤脑组织释放的HMGB1与PCs的CD24受体结合，抑制PCs功能，导致肠道菌群紊乱。本研究明确了TBI后肠道菌群失调的新机制，为临床预防和治疗TBI后肠道菌群失调提供新的靶点和数据支持。