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Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm.

  • Hugelshofer M Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • Buzzi RM Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Schaer CA Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Richter H Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
  • Akeret K Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • Anagnostakou V Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • Mahmoudi L Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Vaccani R Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Vallelian F Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Deuel JW Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Kronen PW Veterinary Anaesthesia Services - International, Winterthur, Switzerland.
  • Kulcsar Z Department of Neuroradiology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • Regli L Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
  • Baek JH Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
  • Pires IS William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA.
  • Palmer AF William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA.
  • Dennler M Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
  • Humar R Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
  • Buehler PW Center of Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
  • Kircher PR Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
  • Keller E Neurointensive Care Unit, University Hospital of Zurich, Zurich, Switzerland.
  • Schaer DJ Division of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.
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  • 2019-08-28
Published in:
  • The Journal of clinical investigation. - 2019
Cardiovascular disease
Neuroscience
Nitric oxide
Stroke
Vascular Biology
Animals
Basilar Artery
Brain
Cerebrospinal Fluid
Disease Models, Animal
Female
Haptoglobins
Hemoglobins
Humans
Intracranial Aneurysm
Male
Mice
Mice, Inbred C57BL
Proteomics
Sheep
Signal Transduction
Subarachnoid Hemorrhage
Subarachnoid Space
Swine
Vasospasm, Intracranial
English Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/11735
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