Microvascular Thrombosis in systemic inflammation

弥散性血管内凝血(DIC)见于25%-50%的脓毒症患者。 DIC可导致微血管血栓形成，从而导致多器官功能障碍 综合征(MODS)和死亡。尽管在过去五年中取得了重大进展 在过去十年的脓毒症管理中，脓毒症的死亡率仍然很高(30%的死亡率)和 在脓毒症引起的多器官功能障碍综合征患者中更大。目前，还没有治疗的方法 脓毒症所致DIC。在目前的资助期间，我们开发了一种猪 临床相关甲氧西林耐药菌致DIC模型的建立 金黄色葡萄球菌(MRSA)菌株。研究人员对这些动物进行了长达70小时的研究。 通过使用这种新的加长猪模型，我们观察到 静脉注射后外周血循环中的波形蛋白(即血浆波形蛋白) 接种细菌。这一在败血症猪身上的有趣发现证实了蛋白质组学 研究表明，败血症患者的血浆Vim水平升高。这些研究 验证了猪和人类疾病发展的相似性。在信号期间 在猪模型的转导研究中，我们观察到MRSA侮辱提高了PRO-1。 炎症信号，丝氨酸磷酸化血浆Vim水平和 降低蛋白磷酸酶2A的活性。此外，我们的研究表明， 外源性Vim增强凝血酶诱导的纤维蛋白聚合，这一过程可以 导致脓毒症所致DIC的微血管血栓形成和凝血障碍。这个 该项目的目标是使用人类败血症血浆和细菌诱导的系统 猪炎症模型的建立及血浆Vim可能的作用机制 在凝血障碍和促进促炎信号方面。我们将使用多个PI 探讨并提出三个目标：目标1将描述结构特征和活动 并确定其在凝血障碍中的作用。目标2将 询问血浆Vim在细菌致炎信号中的作用- 引起全身炎症。目的3将研究血浆Vim在脓毒症中的作用。 用细菌性败血症猪模型和人败血症受试者诱导DIC。成功 这些研究的完成将揭示血浆Vim增加的新机制 促进微血管血栓形成和促炎信号。这项研究具有 将血浆Vim确定为脓毒症的新指标和治疗靶点的可能性- 诱发性DIC。

Disseminated intravascular coagulation (DIC) is manifested in 25-50% of septic patients. DIC can cause microvascular thrombosis, which leads to multiple organ dysfunction syndrome (MODS) and death. Although significant progress has been made during the past decade in sepsis management, sepsis mortality remains high (>30% mortality) and is greater in patients with sepsis-induced MODS. Currently, there is no treatment for sepsis-induced DIC. During the present funding period, we have developed a porcine model for bacteria-induced DIC using a clinically relevant Methicillin-Resistant Staphylococcus aureus (MRSA) strain. These animals were studied for up to 70 hours. By using this novel lengthen porcine model, we observed a marked increment in peripheral blood circulating vimentin (namely plasma Vim) after the intravenous inoculation of the bacteria. This intriguing finding in septic pigs confirmed proteomics studies that showed increased plasma Vim levels in septic human patients. These studies validated the similarity of disease progression in pigs and humans. During signal transduction studies in porcine model, we observed that MRSA insult elevated pro- inflammatory signaling, increased serine phosphorylated plasma Vim levels and decreased the activity of protein phosphatase 2A. Moreover, our studies showed that exogenous Vim potentiated thrombin-induced fibrin polymerization, a process that can contribute to microvascular thrombosis and coagulopathy in sepsis-induced DIC. The goal of this project is to use human septic plasma and bacteria-induced systemic inflammation model in pigs and investigate the potential mechanistic role for plasma Vim in coagulopathy and in promoting pro-inflammatory signaling. We will employ a multi-PI approach and propose three aims: Aim 1 will characterize structural features and activity of plasma vimentin and determine how it contributes to coagulopathy. Aim 2 will interrogate the function of plasma Vim in pro-inflammatory signaling during bacteria- induced systemic inflammation. Aim 3 will investigate the role of plasma Vim in sepsis- induced DIC using bacterial sepsis porcine model and human sepsis subjects. Successful completion of these studies will reveal new mechanisms for the increased plasma Vim in promoting microvascular thrombosis and pro-inflammatory signaling. The study has the potential to identify plasma Vim as a new indicator and therapeutic target for sepsis- induced DIC.