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.
This proposal will characterize the novel interaction of circulating vimentin in blood with fibrin to support thrombosis and the potential of vimentin to promote signaling during systemic inflammation. This work will test a therapy for microvascular thrombosis using a porcine model for bacteria-induced sepsis, laying the basis for the development of potential anti-inflammatory/thrombosis agents targeting plasma vimentin and/or fibrin in inflammation.
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