Mechanisms of C-Reactive Protein-Induced Blood-Brain Barrier Disruption

作者：Kuhlmann Christoph R W; Librizzi Laura; Closhen Dorothea; Pflanzner Thorsten; Lessmann Volkmar; Pietrzik Claus U; de Curtis Marco; Luhmann Heiko J^*

来源：Stroke, 2009, 40(4): 1458-1466.

DOI：10.1161/STROKEAHA.108.535930

• blood-brain barrier
• edema
• myosin light chain
• stroke

Background and Purpose-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 mu g/mL) causes a disruption of the blood-brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fc gamma 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. (Stroke. 2009;40:1458-1466.)

• 出版日期2009-4