Plasminogen activator inhibitor-1 augments damage by impairing fibrinolysis after traumatic brain injury.

Autor: Griemert EV; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Schwarzmaier SM; Department of Anesthesiology, Ludwig-Maximilians-University (LMU) Munich Medical Center, Munich, Germany., Hummel R; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Gölz C; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Yang D; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Neuhaus W; Austrian Institute of Technology, Department Health and Environment, Molecular Diagnostics, Vienna, Austria., Burek M; Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany., Förster CY; Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany., Petkovic I; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Trabold R; Institute for Surgical Research at the Walter Brendel Center of Experimental Medicine, University of Munich Medical Center, Munich, Germany., Plesnila N; Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians-University (LMU) Munich Medical Center, Munich, Germany and Munich Cluster for Systems Neurology (Synergy), Munich, Germany., Engelhard K; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Schäfer MK; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany.; Focus Program Translational Neuroscience, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany., Thal SC; Department of Anesthesiology, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany.; Focus Program Translational Neuroscience, University Medical Center of Johannes-Gutenberg-University Mainz, Mainz, Germany.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2019 May; Vol. 85 (5), pp. 667-680. Date of Electronic Publication: 2019 Mar 30.
DOI: 10.1002/ana.25458
Abstrakt: Objective: Plasminogen activator inhibitor-1 (PAI-1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI-1 mediates post-traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI-1 attenuating clot formation and lesion expansion after brain trauma.
Methods: We evaluated PAI-1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI-1 with PAI-039 and stimulation by tranexamic acid, and we confirmed our results in PAI-1-deficient animals.
Results: PAI-1 mRNA was time-dependently upregulated, with a 305-fold peak 12 hours after CCI, which effectively counteracted the 2- to 3-fold increase in cerebral tissue-type/urokinase plasminogen activator expression. PAI-039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post-traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI-1-deficient mice, the therapeutic effect of PAI-039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle.
Interpretation: This study identifies impaired fibrinolysis as a critical process in post-traumatic secondary brain damage and suggests that PAI-1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667-680.
(© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)
Databáze: MEDLINE
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