Microvascular Leakage in Hemorrhagic Shock and Trauma

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This R35 MIRA grant application addresses a fundamental gap in understanding of the mechanisms that underlie trauma-induced microvascular leakage, a hallmark of the systemic inflammatory response. The long-term goal is to identify novel targets that can be used to ameliorate microvascular leakage in the context of traumatic injury, in order to improve outcomes for trauma patients. To achieve this goal, the current knowledge of the cellular and molecular signals that control microvascular permeability must be significantly expanded, including signals that promote hyperpermeability and those that promote resolution toward normal barrier function. Also, very little is known about how alcohol intoxication, which often accompanies traumatic injury, worsens microvascular leakage leading to poorer outcomes for trauma patients. Until these gaps in knowledge are filled, physicians will not be able to shift beyond current therapeutic paradigms to the next level of care required to save many patients that worsen over time after trauma, developing sepsis and multiple organ failure. To significantly expand the current knowledge base of how microvascular hyperpermeability develops and is resolved, the proposed research capitalizes on emerging approaches that have become more widely available. These include RNA-Seq, proteomics, metabolomics, and lipidomics, which provide unbiased analysis of changes in expression of genes and the molecular landscape. Applying these methods to experimental models of trauma or cells/tissues from trauma patients will identify novel molecules associated with trauma-induced microvascular hyperpermeability that will reveal answers to three key questions that must be addressed in order to advance new therapies: 1) Which endothelial signals activated by alcohol intoxication and hemorrhagic shock sustain increased microvascular leakage, and which terminate microvascular hyperpermeability? 2) Can sustained microvascular hyperpermeability be accurately predicted and monitored using plasma biomarkers of endothelial injury or leukocyte activation, to help guide therapeutic interventions? 3) How can fluid resuscitation be optimized to reduce microvascular hyperpermeability, improve blood-tissue exchange, and better prevent organ dysfunction? A multilevel approach will be used to answer these questions featuring an established, clinically relevant rodent model of combined alcohol intoxication and hemorrhagic shock/resuscitation, supported by cultured endothelial cell models that will increase the depth of understanding about how the microvascular endothelium responds to trauma/shock. This proposal also leverages the PI’s unique expertise with isolating intact venules for study, and to maximize translational impact will utilize a novel human isolated venule permeability model. Finding answers to these key questions is important, because having comprehensive knowledge of the signals that activate and terminate microvascular hyperpermeability, the biomarkers involved, or what key factors in plasma are endothelial barrier-protective, will permit logical development of new, personalized therapeutic strategies to extend and improve life.