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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101927-02
Application #
8517149
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2012-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$269,372
Indirect Cost
$86,022
Name
University of Alabama Birmingham
Department
Surgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Ham 3rd, P Benson; Raju, Raghavan (2016) Mitochondrial function in hypoxic ischemic injury and influence of aging. Prog Neurobiol :
Ayub, Ahmar; Poulose, Ninu; Raju, Raghavan (2015) Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock. Mol Med 21:305-12
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
Jian, Bixi; Yang, Shaolong; Chaudry, Irshad H et al. (2014) Resveratrol restores sirtuin 1 (SIRT1) activity and pyruvate dehydrogenase kinase 1 (PDK1) expression after hemorrhagic injury in a rat model. Mol Med 20:10-6