title: Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury.
abstract: Endothelin-1 (ET-1), tissue plasminogen activator (tPA), and extracellular signal-regulated kinases-mitogen activated protein kinase (ERK-MAPK) are mediators of impaired cerebral hemodynamics after fluid percussion brain injury (FPI) in piglets. Microparticles (MPs) are released into the circulation from a variety of cells during stress, are pro-thrombotic and pro-inflammatory, and may be lysed with polyethylene glycol telomere B (PEG-TB). We hypothesized that MPs released after traumatic brain injury impair hypotensive cerebrovasodilation and that PEG-TB protects the vascular response via MP lysis, and we investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process. FPI was induced in piglets equipped with a closed cranial window. Animals received PEG-TB or saline (vehicle) 30-minutes post-injury. Serum and cerebrospinal fluid (CSF) were sampled and pial arteries were measured pre- and post-injury. MPs were quantified by flow cytometry. CSF samples were analyzed with enzyme-linked immunosorbent assay. MP levels, vasodilatory responses, and CSF signaling assays were similar in all animals prior to injury and treatment. After injury, MP levels were elevated in the serum of vehicle but not in PEG-TB-treated animals. Pial artery dilation in response to hypotension was impaired after injury but protected in PEG-TB-treated animals. After injury, CSF levels of tPA, ET-1, and ERK-MAPK were all elevated, but not in PEG-TB-treated animals. PEG-TB-treated animals also showed reduction in neuronal injury in CA1 and CA3 hippocampus, compared with control animals. These results show that serum MP levels are elevated after FPI and lead to impaired hypotensive cerebrovasodilation via over-expression of tPA, ET-1, and ERK-MAPK. Treatment with PEG-TB after injury reduces MP levels and protects hypotensive cerebrovasodilation and limits hippocampal neuronal cell injury.
authors.affiliation: 1 Department of Neurosurgery, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Leif-Erik
authors.initials: LE
authors.lastname: Bohman
authors.affiliation: 2 Department of Anesthesiology and Critical Care, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.affiliation: 3 Department of Emergency Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.|5 Institute for Environmental Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Tatyana N
authors.initials: TN
authors.lastname: Milovanova
authors.affiliation: 1 Department of Neurosurgery, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sanborn
authors.affiliation: 3 Department of Emergency Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.|5 Institute for Environmental Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.affiliation: 2 Department of Anesthesiology and Critical Care, University of Pennsylvania , Philadelphia, Pennsylvania.|4 Department of Pharmacology, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology*; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000473:pathology*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000134:cerebrospinal fluid*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000134:cerebrospinal fluid*; D005260:Female; D007022:Hypotension / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D008297:Male; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000134:cerebrospinal fluid*; D014664:Vasodilation / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D048049:Extracellular Signal-Regulated MAP Kinases; D010959:Tissue Plasminogen Activator
keywords: endothelin; fluid percussion injury; hypotensive cerebrovasodilation; microparticles; tissue plasminogen activator; traumatic brain injury