title: Extracellular chromatin is an important mediator of ischemic stroke in mice.
abstract: OBJECTIVE
  Recently, a growing number of studies have revealed a prothrombotic and cytotoxic role for extracellular chromatin. Cerebral ischemia/reperfusion injury is characterized by a significant amount of cell death and neutrophil activation, both of which may result in the release of chromatin. The goal of this study was to assess the effect of extracellular chromatin in ischemic stroke using a mouse model of transient middle cerebral artery occlusion.
  
  
  RESULTS
  Similar to reports in stroke patients, we observed increased levels of circulating nucleosomes and DNA after ischemic stroke in mice. In addition, we observed that general hypoxia also augmented extracellular chromatin. We hypothesized that targeting extracellular chromatin components would be protective in ischemic stroke. Indeed, treatment with recombinant human DNase 1 significantly improved stroke outcome. Neutralization of histones using an antihistone antibody was also protective as evidenced by smaller infarct volumes, whereas increasing levels of extracellular histones via histone infusion exacerbated stroke outcome by increasing infarct size and worsening functional outcome.
  
  
  CONCLUSIONS
  Our results indicate that extracellular chromatin is generated and is detrimental during cerebral ischemia/reperfusion in mice. Targeting DNA and histones may be a new therapeutic strategy to limit injury resulting from ischemic stroke.
authors.affiliation: Immune Disease Institute, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Simon F
authors.initials: SF
authors.lastname: De Meyer
authors.forename: Georgette L
authors.initials: GL
authors.lastname: Suidan
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology*; D002843:Chromatin / Q000502:physiology*; D003850:Deoxyribonuclease I / Q000627:therapeutic use; D006657:Histones / Q000037:antagonists & inhibitors; D000860:Hypoxia / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000502:physiology; D020521:Stroke / Q000188:drug therapy / Q000209:etiology*
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D003850:Deoxyribonuclease I