Genomic profiles of damage and protection in human intracerebral hemorrhage.
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.
Carmichael
S Thomas
ST
Department of Neurology, Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. scarmichael@mednet.ucla.edu
Vespa
Paul M
PM
Saver
Jeffery L
JL
Coppola
Giovanni
G
Geschwind
Daniel H
DH
Starkman
Sidney
S
Miller
Chad M
CM
Kidwell
Chelsea S
CS
Liebeskind
David S
DS
Martin
Neil A
NA
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D019060:Minimally Invasive Surgical Procedures / Q000592:standards; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012449:Safety
D009419:Nerve Tissue Proteins; D012313:RNA