Endothelial injury and repair following hemorrhagic shock

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Project Summary/Abstract Trauma is the third leading cause of death. Of these deaths, hemorrhage remains the number one cause of early trauma deaths, though reductions in early mortality have occurred from modern resuscitation strategies. Further reductions in early deaths and later reductions in multi-organ failure (MOF) in survivors of hemorrhage represent opportunities to further improve care after hemorrhagic shock (HS). Our efforts are focused on reversal of the dysfunctional endothelium that follows trauma and HS, coined the “endotheliopathy of trauma” (EoT). We were the first to demonstrate in patients that syndecan-1 (Sdc1), a cell surface proteoglycan, is shed after trauma and that shedding was associated with poor outcomes. However, much less is known about Sdc1 expression and its effect on the endothelium, representing a gap in our knowledge. In our efforts to define the mechanisms for Sdc1 downregulation, we discovered that microRNA-19b (miR-19b) targets Sdc1, phenocopies the effects of HS in reducing Sdc1 expression, and contributes to the EoT, novel observations. Our data also demonstrates that miR-19b may be a therapeutic target, as antagomiRs reverse the deleterious effects of Sdc1 downregulation. We will also show that fibrinogen, as a key component in plasma and as an isolated therapeutic, co-localizes and engages Sdc1 on the endothelial cell surface to enhance Sdc1 expression, reduce miR-19b expression, and restore barrier integrity. Low systemic concentrations of fibrinogen after trauma are associated with increased severity of injury and are predictive of mortality. Nonetheless, in the US standard practice is to replace fibrinogen (using cryoprecipitate) only once levels are depressed and late during massive transfusion. Results of this study will support a major change in practice to include the early use of fibrinogen as an endothelial protector to lessen MOF and decrease mortality. Our preliminary data support the novel hypothesis that miRNA-19b-induced downregulation of Sdc1 following HS leads to breakdown of endothelial cell barrier integrity. We further hypothesize that fibrinogen restores endothelial cell Sdc1 expression by inhibiting miR-19b, engaging with Sdc1 on the cell surface, and activating PAK1 to restore barrier integrity and mitigate lung injury. We will test our hypotheses by pursuing the following aims: SA 1. Determine the role of miR-19b on endothelial cell Sdc1 downregulation following hemorrhagic shock and the pulmonary protective effects of miR-19b antagomiRs and SA2. Examine the mechanism by which fibrinogen enhances endothelial cell Sdc1 expression and mitigates lung injury after hemorrhagic shock. Our proposal puts forth innovative concepts and novel mechanisms that offer a new paradigm for the reversal of the EOT. This has significant implication to hemorrhagic shock pathogenesis and treatment, and miRNA biology along with the potential to improve outcomes and reduce deaths after hemorrhagic shock.