Modulation of Pulmonary Vascular Permeability and Inflammation by Mesenchymal Stem Cells (MSCs) in Hemorrhagic Shock

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 DESCRIPTION (provided by applicant): Traumatic injury is the leading cause of death and disability in children and adults worldwide in both civilian and military populations.5 One of the hallmarks of hemorrhagic shock (HS), a condition resulting from rapid blood loss after traumatic injury, is the onset of a systemic response that results in endothelial injury, inflammation, aberrant coagulation, tissue edema and end organ injury. HS is associated with a high incidence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (14-20% of ICU patients) that results in significant morbidity and mortality.8, 9 8-13 Aside from resuscitatio paradigms and supportive therapy there are currently few treatments to treat lung edema and ARDS in trauma.14 Mesenchymal stem cells (MSCs) have been shown to have therapeutic potential in multiple conditions characterized by vascular compromise, and inflammation.1, 15-31 Our group has shown that IV MSCs attenuate blood brain barrier (BBB) permeability after traumatic brain injury (TBI) and also lung permeability and inflammation after HS.1, 15 The mechanisms of how MSCs work are largely unknown. Many groups including our own have shown that the beneficial effects of MSCs are mediated by soluble factors.4, 32 In our past studies, we identified a soluble factor produced and induced by MSCs - TIMP3 (Tissue Inhibitor of Matrix Metalloproteinase-3) - that can recapitulate the protective effects of MSCs on endothelial permeability by modulating endothelial adherens junctions and vascular stability. In our current studies, we have evidence suggesting that TIMP3 can separately modulate pulmonary vascular permeability induced by hemorrhagic shock. Our data support the hypothesis that TIMP3 tightens the blood-lung vascular barrier. Our overall mechanistic hypothesis is that intravenous (IV) MSCs decrease lung permeability, lung edema and improve lung function through production and induction of TIMP3 after HS. We hypothesize that IV TIMP3 will recapitulate the protective effects of IV MSCs. It is our goal to define the mechanisms of action of MSCs in hemorrhagic shock induced vascular permeability and inflammation and to investigate the role and therapeutic potential of the MSC derived protein - TIMP3. Aim 1 is an in vitro aim that is designed to elucidate mechanisms of action of TIMP3 through investigations of function, domains and signaling pathways involved in TIMP3 and MSC mediated effects on pulmonary endothelial permeability. Aim 2 is designed to answer the question of whether IV MSCs (with and without TIMP3 expression) and TIMP3 attenuate HS induced lung permeability using an established mouse model of hemorrhagic shock and trauma. Aim 3 is designed to study the effects of TIMP3 and MSCs in the TIMP3 knock-out mouse. The final long-term goal of our research effort in this area is to translate our findings from "bench t bedside" to provide a treatment option in trauma that can mitigate patient outcomes.