title: Resuscitation with Valproic Acid Alters Inflammatory Genes in a Porcine Model of Combined Traumatic Brain Injury and Hemorrhagic Shock.
abstract: Traumatic brain injury and hemorrhagic shock (TBI+HS) elicit a complex inflammatory response that contributes to secondary brain injury. There is currently no proven pharmacologic treatment for TBI+HS, but modulation of the epigenome has been shown to be a promising strategy. The aim of this study was to investigate whether valproic acid (VPA), a histone deacetylase inhibitor, modulates the expression of cerebral inflammatory gene profiles in a large animal model of TBI+HS. Ten Yorkshire swine were subjected to computer-controlled TBI+HS (40% blood volume). After 2 h of shock, animals were resuscitated with Hextend (HEX) or HEX+VPA (300 mg/kg, n = 5/group). Six hours after resuscitation, brains were harvested, RNA was isolated, and gene expression profiles were measured using a porcine microarray. Ingenuity Pathway Analysis® (IPA), gene ontology (GO), Parametric Gene Set Enrichment Analysis (PGSEA), and DAVID (Database for Annotation, Visualization, and Integrated Discovery) were used for pathway analysis. Key microarray findings were verified using real-time polymerase chain reaction (PCR). IPA analysis revealed that VPA significantly down-regulated the complement system (p < 0.001), natural killer cell communication (p < 0.001), and dendritic cell maturation (p < 0.001). DAVID analysis indicated that a cluster of inflammatory pathways held the highest rank and gene enrichment score. Real-time PCR data confirmed that VPA significantly down-expressed genes that ultimately regulate nuclear factor-kB (NF-kB)-mediated production of cytokines, such as TYROBP, TREM2, CCR1, and IL-1β. This high-throughput analysis of cerebral gene expression shows that addition of VPA to the resuscitation protocol significantly modulates the expression of inflammatory pathways in a clinically realistic model of TBI+HS.
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
authors.forename: Ted
authors.initials: T
authors.lastname: Bambakidis
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.|2 Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam, the Netherlands .
authors.forename: Simone E
authors.initials: SE
authors.lastname: Dekker
authors.affiliation: 3 Department of Surgical Gastroenterology, Copenhagen University Hospital , Copenhagen, Denmark .
authors.forename: Martin
authors.initials: M
authors.lastname: Sillesen
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.affiliation: 4 DNA Sequencing Core, University of Michigan , Ann Arbor, Michigan.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Johnson
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.affiliation: 5 Department of Molecular Cell Biology and Immunology, VU University Medical Center , Amsterdam, the Netherlands .
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy / Q000378:metabolism*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D010952:Plasma Substitutes / Q000008:administration & dosage / Q000494:pharmacology*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy / Q000378:metabolism*; D013552:Swine; D059467:Transcriptome / Q000187:drug effects*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006895:Hydroxyethyl Starch Derivatives; D010952:Plasma Substitutes; D014635:Valproic Acid
keywords: genomics; in vivo studies; inflammation; therapeutic approaches for the treatment of central nervous system injury; traumatic brain injury