Severe hemorrhage causes whole body hypoxia, multiple organ dysfunction and death. Fluid resuscitation is employed to restore organ perfusion and reoxygenation following hemorrhagic injury. Reoxygenation causes oxidative damage and cell and organ injury and there is a need to develop better resuscitation methods to reduce cell injury following hemorrhage. Our systematic study of mitochondrial functional genomics in the rat resulted in the identification of a novel pathway involving Sirt1 (mammalian homolog of sir2-silent mating type information regulation 2) in hemorrhagic injury. Our studies demonstrated a significant decline in Sirt1 expression following trauma-hemorrhage (T- H). Our preliminary data also indicate that resveratrol (trans-3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found i grapes, and an enhancer of Sirt1 activity, reduces heart and liver injury following hemorrhage. Our objective is therefore to establish that resveratrol can be used as an adjunct to resuscitation fluid, following hemorrhage. We will also determine the molecular basis of tissue injury and resveratrol-mediated protection following T-H. Our hypothesis is that resveratrol reduces organ injury following hemorrhagic shock and therefore it can be used as an adjunct to resuscitation fluid. We will test the central hypothesis by pursuing the following four Specific Aims: (1) optimize the time and dose of resveratrol as an adjunct to resuscitation fluid, (2) establish that resveratrol improves survival and reduces organ injury following T-H. (3) determine the effect of resveratrol treatment on cellular energetics following T-H in the heart and the liver, and (4) identify the mediators and mechanism of T-H injury resolution by resveratrol using in vivo and in vitro models. We will use state-of-the-art tools and techniques such as mitochondrial functional genomics and ChIP-chip method to test the hypothesis. When the proposed studies are completed, in addition to identifying resveratrol as an adjunct to resuscitation fluid, we would have also gained new knowledge on molecular pathways involved in hemorrhage injury and their modulation by the antioxidant resveratrol.
T-H injury is a significant health burden as it accounts for up to 40% of trauma-related deaths. Our long-term goal is to develop better therapeutic methods to reduce morbidity and mortality following trauma-hemorrhagic shock.
Hemorrhage accounts for almost half of trauma-related deaths in the United States. Following hemorrhage, fluid resuscitation is employed to restore organ perfusion and reoxygenation. Reoxygenation causes oxidative damage and cell injury. Our objective is to develop better resuscitation methods to reduce tissue damage following hemorrhage. Based upon our preliminary data, we propose that resveratrol, when used as an adjunct to resuscitation fluid, will reduce cell injury following hemorrhage.
|Kvirkvelia, Nino; McMenamin, Malgorzata; Warren, Marie et al. (2018) Kidney-targeted inhibition of protein kinase C-? ameliorates nephrotoxic nephritis with restoration of mitochondrial dysfunction. Kidney Int 94:280-291|
|Subramani, Kumar; Lu, Sumin; Warren, Marie et al. (2017) Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock. Sci Rep 7:2671|
|Ham 3rd, P Benson; Raju, Raghavan (2017) Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol 157:92-116|
|Warren, Marie; Subramani, Kumar; Schwartz, Richard et al. (2017) Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock. Biochim Biophys Acta Mol Basis Dis 1863:2526-2533|
|Raju, Raghavan (2017) Immune and metabolic alterations following trauma and sepsis - An overview. Biochim Biophys Acta Mol Basis Dis 1863:2523-2525|
|Lu, Sumin; Aguilar, Alex; Subramani, Kumar et al. (2016) Alteration of cytokine profile following hemorrhagic shock. Cytokine 81:35-8|
|Poulose, Ninu; Raju, Raghavan (2015) Sirtuin regulation in aging and injury. Biochim Biophys Acta 1852:2442-55|
|Poulose, Ninu; Raju, Raghavan (2014) Aging and injury: alterations in cellular energetics and organ function. Aging Dis 5:101-8|
|Nagineni, Chandrasekharam N; Raju, Raghavan; Nagineni, Krishnasai K et al. (2014) Resveratrol Suppresses Expression of VEGF by Human Retinal Pigment Epithelial Cells: Potential Nutraceutical for Age-related Macular Degeneration. Aging Dis 5:88-100|