title: Tumor necrosis factor-α disruption of brain endothelial cell barrier is mediated through matrix metalloproteinase-9.
abstract: Traumatic brain injuries cause vascular hyperpermeability. Tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), and caspase-3 may be important in these processes but the relationship between them has not been investigated. We hypothesized that TNF-α regulates caspase-3-mediated hyperpermeability and blood brain barrier damage and hyperpermeability directly or indirectly via activation of MMP-9. To test this, rat brain microvascular endothelial cells were treated with TNF-α with or without inhibition of MMP-9. Monolayer permeability was measured, zonula occludens-1 and F-actin configuration were examined, and MMP-9 and caspase-3 activities were quantified. TNF-α increased monolayer permeability, damaged zonula occludens-1, induced filamentous-actin stress fiber formation, and increased both MMP-9 and caspase-3 activities. Inhibition of MMP-9 attenuated these changes. These data highlight a novel link between TNF-α and MMP-9 and show that TNF-α regulated caspase-3-mediated hyperpermeability and vascular damage may be linked to MMP-9 in vitro. These findings augment the understanding of traumatic brain injury and pave the way for improved treatment.
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Wiggins-Dohlvik
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Merriman
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Chinchusha A
authors.initials: CA
authors.lastname: Shaji
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Himakarnika
authors.initials: H
authors.lastname: Alluri
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Marcene
authors.initials: M
authors.lastname: Grimsley
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Davis
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA.
authors.forename: Randall W
authors.initials: RW
authors.lastname: Smith
authors.affiliation: Department of Surgery, Baylor Scott and White Health, Temple, TX, USA; Department of Surgery, Texas A&M University Health Science Center College of Medicine, Temple, TX, USA. Electronic address: btharakan@sw.org.
authors.forename: Binu
authors.initials: B
authors.lastname: Tharakan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000166:cytology*; D001930:Brain Injuries / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9
keywords: Blood brain barrier; Caspase-3; Gelatinase B; Matrix metalloproteinase; Traumatic brain injury; Tumor necrosis factor