title: Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke.
abstract: BACKGROUND
  Blood-brain-barrier (BBB) breakdown and cerebral edema result from postischemic inflammation and contribute to mortality and morbidity after ischemic stroke. A functional role for the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the regulation of reperfusion injury has not yet been demonstrated.
  
  
  OBJECTIVE
  We sought to identify and characterize the relevance of CEACAM1-expressing inflammatory cells in BBB breakdown and outcome after ischemic stroke in Ceacam1(-/-) and wild-type mice.
  
  
  RESULTS
  Focal ischemia was induced by temporary occlusion of the middle cerebral artery with a microfilament. Using MRI and Evans blue permeability assays, we observed increased stroke volumes, BBB breakdown and edema formation, reduction of cerebral perfusion, and brain atrophy in Ceacam1(-/-) mice. This translated into poor performance in neurological scoring and high poststroke-associated mortality. Elevated neutrophil influx, hyperproduction, and release of neutrophil-related matrix metalloproteinase-9 in Ceacam1(-/-) mice were confirmed by immune fluorescence, flow cytometry, zymography, and stimulation of neutrophils. Importantly, neutralization of matrix metalloproteinase-9 activity in Ceacam1(-/-) mice was sufficient to alleviate stroke sizes and improve survival to the level of CEACAM1-competent animals. Immune histochemistry of murine and human poststroke autoptic brains congruently identified abundance of CEACAM1(+)matrix metalloproteinase-9(+) neutrophils in the ischemic hemispheres.
  
  
  CONCLUSIONS
  CEACAM1 controls matrix metalloproteinase-9 secretion by neutrophils in postischemic inflammation at the BBB after stroke. We propose CEACAM1 as an important inhibitory regulator of neutrophil-mediated tissue damage and BBB breakdown in focal cerebral ischemia.
authors.affiliation: From the Institute of Clinical Chemistry, Department of Neurology, Department of Neuropathology, and Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ludewig
authors.forename: Jan
authors.initials: J
authors.lastname: Sedlacik
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.forename: Christian
authors.initials: C
authors.lastname: Bernreuther
authors.forename: Yücel
authors.initials: Y
authors.lastname: Korkusuz
authors.forename: Christoph
authors.initials: C
authors.lastname: Wagener
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.forename: Jens
authors.initials: J
authors.lastname: Fiehler
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Andrea Kristina
authors.initials: AK
authors.lastname: Horst
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001284:Atrophy; D001522:Behavior, Animal; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001929:Brain Edema / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002199:Capillary Permeability; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009043:Motor Activity; D009460:Neurologic Examination; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D006573:Heterocyclic Compounds, 1-Ring; D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: animal model of human disease remodeling; inflammation; ischemic stroke; neutrophils; vascular system injuries