Hyperfibrinolysis increases blood-brain barrier permeability by a plasmin- and bradykinin-dependent mechanism

Blood. 2016 Nov 17;128(20):2423-2434. doi: 10.1182/blood-2016-03-705384. Epub 2016 Aug 16.

Abstract

Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis, and leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood-brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA). As revealed by near-infrared fluorescence imaging, hyperfibrinolytic mice presented a significant increase in BBB permeability. Using a set of deletion variants of tPA and pharmacological approaches, we demonstrated that this effect was independent of N-methyl-D-aspartate receptor, low-density lipoprotein-related protein, protease-activated receptor-1, or matrix metalloproteinases. In contrast, we provide evidence that hyperfibrinolysis-induced BBB leakage is dependent on plasmin-mediated generation of bradykinin and subsequent activation of bradykinin B2 receptors. Accordingly, this effect was prevented by icatibant, a clinically available B2 receptor antagonist. In agreement with these preclinical data, bradykinin generation was also observed in humans in a context of acute pharmacological hyperfibrinolysis. Altogether, these results suggest that B2 receptor blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Bradykinin / metabolism
  • Bradykinin / physiology*
  • Bradykinin B2 Receptor Antagonists / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Capillary Permeability / drug effects
  • Capillary Permeability / genetics
  • Capillary Permeability / physiology*
  • Fibrinolysin / metabolism
  • Fibrinolysin / physiology*
  • Fibrinolysis / drug effects
  • Fibrinolysis / genetics
  • Fibrinolysis / physiology*
  • Hydrodynamics
  • Mice
  • Mice, Transgenic
  • Receptor, Bradykinin B2 / genetics
  • Receptor, Bradykinin B2 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism

Substances

  • Bradykinin B2 Receptor Antagonists
  • Receptor, Bradykinin B2
  • Tissue Plasminogen Activator
  • Fibrinolysin
  • Bradykinin