Genomic profiles of damage and protection in human intracerebral hemorrhage.

TitleGenomic profiles of damage and protection in human intracerebral hemorrhage.
Publication TypeJournal Article
Year of Publication2008
AuthorsCarmichael, TS, Vespa PM, Saver JL, Coppola G, Geschwind DH, Starkman S, Miller CM, Kidwell CS, Liebeskind DS, Martin NA
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Volume28
Issue11
Pagination1860-75
Date Published2008 Nov
ISSN1559-7016
KeywordsAnimals, Brain, Cerebral Hemorrhage, Clinical Trials as Topic, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Humans, Magnetic Resonance Imaging, Mice, Nerve Tissue Proteins, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, RNA, Safety, Surgical Procedures, Minimally Invasive
Abstract

Intracerebral hemorrhage (ICH) produces a high rate of death and disability. The molecular mechanisms of damage in perihematomal tissue in humans have not been systematically characterized. This study determines the gene expression profile and molecular networks that are induced in human perihematomal tissue through molecular analysis of tissue obtained from endoscopic clot evacuation. Differentially expressed genes and their cellular origin were confirmed in a mouse model of ICH. A total of 624 genes showed altered regulation in human ICH. Bioinformatic analysis shows that these genes form interconnected networks of proinflammatory, anti-inflammatory, and neuronal signaling cascades. Intracerebral hemorrhage evokes coordinated upregulation of proinflammatory signaling through specific cytokines and chemokines and their downstream molecular pathways. Anti-inflammatory networks are also induced by ICH, including annexins A1 and A2 and transforming growth factor beta (TGFbeta) and their intracellular cascades. Intracerebral hemorrhage downregulates many neuronal signaling systems, including the N-methyl-D-aspartic acid (NMDA) receptor complex and membrane ion channels. Select portions of these molecular networks were confirmed in the mouse, and the proteins in a subset of these networks localized to subsets of neurons, oligodendrocytes, or leukocytes. These inflammatory and anti-inflammatory networks interact at several key points in neutrophil signaling, apoptotic cell death, and protease responses, and indicate that secondary damage in ICH activates opposing molecular systems.

DOI10.3928/01913913-20090706-05
Alternate JournalJ. Cereb. Blood Flow Metab.