Effect of pharmacologic resuscitation on the brain gene expression profiles in a swine model of traumatic brain injury and hemorrhage

作者：Dekker Simone E; Bambakidis Ted; Sillesen Martin; Liu Baoling; Johnson Craig N; Jin Guang; Li Yongqing; Alam Hasan B^*

来源：Journal of Trauma and Acute Care Surgery, 2014, 77(6): 906-912.

DOI：10.1097/TA.0000000000000345

• Injury
• brain
• genes
• apoptosis
• hemorrhage
• pigs

BACKGROUND: We have previously shown that addition of valproic acid (VPA; a histone deacetylase inhibitor) to hetastarch (Hextend [HEX]) resuscitation significantly decreases lesion size in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). However, the precise mechanisms have not been well defined. As VPA is a transcriptional modulator, the aim of this study was to investigate its effect on brain gene expression profiles. %26lt;br%26gt;METHODS: Swine were subjected to controlled TBI and HS (40% blood volume), kept in shock for 2 hours, and resuscitated with HEX or HEX + VPA (n = 5 per group). Following 6 hours of observation, brain RNA was isolated, and gene expression profiles were measured using a Porcine Gene ST 1.1 microarray (Affymetrix, Santa Clara, CA). Pathway analysis was done using network analysis tools Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis. Real-time polymerase chain reaction was used to verify the key microarray findings. %26lt;br%26gt;RESULTS: A total of 1,668 probe sets mapping to 370 known genes were differentially expressed between the HEX and HEX + VPA groups. Expression of apoptotic genes differed between groups, and biologic function analysis predicted a significant downregulation of apoptosis (p = 1.29 x 10(-12)), cell death (p = 8.46 x 10(-12)), and necrosis (p = 9.07 x 10(-11)). Pathway analysis indicated a significant modulation of pathways involved in cell signaling, dendritic cell response, and the complement system. %26lt;br%26gt;CONCLUSION: This is the first high-throughput analysis of cerebral gene profiling following TBI + HS. It shows that treatment with VPA significantly alters early transcription of pathways related to cell survival, which may explain its neuroprotective effects.

• 出版日期2014-12