title: Mechanisms of C-reactive protein-induced blood-brain barrier disruption.
abstract: OBJECTIVE
  Increased mortality after stroke is associated with brain edema formation and high plasma levels of the acute phase reactant C-reactive protein (CRP). The aim of this study was to examine whether CRP directly affects blood-brain barrier stability and to analyze the underlying signaling pathways.
  
  
  METHODS
  We used a cell coculture model of the blood-brain barrier and the guinea pig isolated whole brain preparation.
  
  
  RESULTS
  We could show that CRP at clinically relevant concentrations (10 to 20 microg/mL) causes a disruption of the blood-brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fcgamma receptors CD16/32 followed by p38-mitogen-activated protein kinase-dependent reactive oxygen species formation by the NAD(P)H-oxidase. The resulting oxidative stress increased myosin light chain kinase activity leading to an activation of the contractile machinery. Blocking myosin light chain phosphorylation prevented the CRP-induced blood-brain barrier breakdown and the disruption of tight junctions.
  
  
  CONCLUSIONS
  Our data identify a previously unrecognized mechanism linking CRP and brain edema formation and present a signaling pathway that offers new sites of therapeutic intervention.
authors.affiliation: Institute of Physiology and Pathophysiology, Johannes Gutenberg University of Mainz, Mainz, Germany. luhmann@uni-mainz.de
authors.forename: Christoph R W
authors.initials: CR
authors.lastname: Kuhlmann
authors.forename: Laura
authors.initials: L
authors.lastname: Librizzi
authors.forename: Dorothea
authors.initials: D
authors.lastname: Closhen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pflanzner
authors.forename: Volkmar
authors.initials: V
authors.lastname: Lessmann
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.forename: Marco
authors.initials: M
authors.lastname: de Curtis
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Luhmann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001929:Brain Edema / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000378:metabolism; D006168:Guinea Pigs; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018994:Myosin Light Chains; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases