Patrick Garland1, Andrew J Durnford1, Azubuike I Okemefuna1, John Dunbar1, James A R Nicoll1, James Galea1, Delphine Boche1, Diederik O Bulters1, Ian Galea2. 1. From the Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom (P.G., J.D., J.A.R.N., D.B., D.O.B., I.G.); Neurosurgery, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (A.J.D., D.O.B., I.G.); R&D, Bio Products Laboratory Limited, Hertfordshire, United Kingdom (A.I.O.); and the Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (J.G.). 2. From the Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom (P.G., J.D., J.A.R.N., D.B., D.O.B., I.G.); Neurosurgery, Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (A.J.D., D.O.B., I.G.); R&D, Bio Products Laboratory Limited, Hertfordshire, United Kingdom (A.I.O.); and the Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (J.G.). I.Galea@soton.ac.uk.
Abstract
BACKGROUND AND PURPOSE: Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after hemorrhage. METHODS: Using cerebrospinal fluid and tissue from patients with SAH and control individuals, the activity of the intracranial CD91-hemopexin system was examined using ELISA, ultrahigh performance liquid chromatography, and immunohistochemistry. RESULTS: In control individuals, cerebrospinal fluid hemopexin was mainly synthesized intrathecally. After SAH, cerebrospinal fluid hemopexin was high in one third of cases, and these patients had a higher probability of delayed cerebral ischemia and poorer neurological outcome. The intracranial CD91-hemopexin system was active after SAH because CD91 positively correlated with iron deposition in brain tissue. Heme-hemopexin uptake saturated rapidly after SAH because bound heme accumulated early in the cerebrospinal fluid. When the blood-brain barrier was compromised after SAH, serum hemopexin level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. CONCLUSIONS: The CD91-heme-hemopexin scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target.
BACKGROUND AND PURPOSE: Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after hemorrhage. METHODS: Using cerebrospinal fluid and tissue from patients with SAH and control individuals, the activity of the intracranial CD91-hemopexin system was examined using ELISA, ultrahigh performance liquid chromatography, and immunohistochemistry. RESULTS: In control individuals, cerebrospinal fluid hemopexin was mainly synthesized intrathecally. After SAH, cerebrospinal fluid hemopexin was high in one third of cases, and these patients had a higher probability of delayed cerebral ischemia and poorer neurological outcome. The intracranial CD91-hemopexin system was active after SAH because CD91 positively correlated with iron deposition in brain tissue. Heme-hemopexin uptake saturated rapidly after SAH because bound heme accumulated early in the cerebrospinal fluid. When the blood-brain barrier was compromised after SAH, serum hemopexin level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. CONCLUSIONS: The CD91-heme-hemopexin scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target.
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