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Resuscitation with Valproic Acid Alters Inflammatory Genes in a Porcine Model of Combined Traumatic Brain Injury and Hemorrhagic Shock.
Bambakidis, Ted; Dekker, Simone E; Sillesen, Martin; Liu, Baoling; Johnson, Craig N; Jin, Guang; de Vries, Helga E; Li, Yongqing; Alam, Hasan B.
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  • Bambakidis T; 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
  • Dekker SE; 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
  • Sillesen M; 2 Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam, the Netherlands .
  • Liu B; 3 Department of Surgical Gastroenterology, Copenhagen University Hospital , Copenhagen, Denmark .
  • Johnson CN; 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
  • Jin G; 4 DNA Sequencing Core, University of Michigan , Ann Arbor, Michigan.
  • de Vries HE; 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
  • Li Y; 5 Department of Molecular Cell Biology and Immunology, VU University Medical Center , Amsterdam, the Netherlands .
  • Alam HB; 1 Department of Surgery, University of Michigan Hospital , Ann Arbor, Michigan.
J Neurotrauma ; 33(16): 1514-21, 2016 08 15.
Article en En | MEDLINE | ID: mdl-26905959
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-1ß. 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resucitación / Choque Hemorrágico / Encéfalo / Citocinas / Ácido Valproico / Sustitutos del Plasma / Inhibidores Enzimáticos / Transcriptoma / Lesiones Traumáticas del Encéfalo Tipo de estudio: Guideline / Prognostic_studies Límite: Animals Idioma: En Revista: J Neurotrauma Asunto de la revista: NEUROLOGIA / TRAUMATOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resucitación / Choque Hemorrágico / Encéfalo / Citocinas / Ácido Valproico / Sustitutos del Plasma / Inhibidores Enzimáticos / Transcriptoma / Lesiones Traumáticas del Encéfalo Tipo de estudio: Guideline / Prognostic_studies Límite: Animals Idioma: En Revista: J Neurotrauma Asunto de la revista: NEUROLOGIA / TRAUMATOLOGIA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos