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Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation

Academic Article
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Overview

authors

  • del Zoppo, G. J.
  • Frankowski, H.
  • Gu, Y. H.
  • Osada, T.
  • Kanazawa, M.
  • Milner, Richard
  • Wang, X. Y.
  • Hosomi, N.
  • Mabuchi, T.
  • Koziol, James

publication date

  • May 2012

journal

  • Journal of Cerebral Blood Flow and Metabolism  Journal

abstract

  • Hemorrhage and edema accompany evolving brain tissue injury after ischemic stroke. In patients, these events have been associated with metalloproteinase (MMP)-9 in plasma. Both the causes and cellular sources of MMP-9 generation in this setting have not been defined. MMP-2 and MMP-9 in nonhuman primate tissue in regions of plasma leakage, and primary murine microglia and astrocytes, were assayed by immunocytochemistry, zymography, and real-time RT-PCR. Ischemia-related hemorrhage was associated with microglial activation in vivo, and with the leakage of plasma fibronectin and vitronectin into the surrounding tissue. In strict serum-depleted primary cultures, by zymography, pro-MMP-9 was generated by primary murine microglia when exposed to vitronectin and fibronectin. Protease secretion was enhanced by experimental ischemia (oxygen-glucose deprivation, OGD). Primary astrocytes, on each matrix, generated only pro-MMP-2, which decreased during OGD. Microglia-astrocyte contact enhanced pro-MMP-9 generation in a cell density-dependent manner under normoxia and OGD. Compatible with observations in a high quality model of focal cerebral ischemia, microglia, but not astrocytes, respond to vitronectin and fibronectin, found when plasma extravasates into the injured region. Astrocytes alone do not generate pro-MMP-9. These events explain the appearance of MMP-9 antigen in association with ischemia-induced cerebral hemorrhage and edema.

subject areas

  • Animals
  • Astrocytes
  • Brain Edema
  • Brain Ischemia
  • Cell Hypoxia
  • Cells, Cultured
  • Enzyme Precursors
  • Fibronectins
  • Gelatinases
  • Humans
  • Intracranial Hemorrhages
  • Matrix Metalloproteinase 9
  • Mice
  • Microglia
  • Papio anubis
  • Vitronectin
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Research

keywords

  • hemorrhage
  • ischemic stroke
  • metalloproteinases
  • microglia
  • microvascular dysfunction
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Identity

PubMed Central ID

  • PMC3345906

International Standard Serial Number (ISSN)

  • 0271-678X

Digital Object Identifier (DOI)

  • 10.1038/jcbfm.2012.11

PubMed ID

  • 22354151
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Additional Document Info

start page

  • 919

end page

  • 932

volume

  • 32

issue

  • 5

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