title: Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus.
abstract: The blood-brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood-brain barrier. Hypoxic-ischemic damage to the blood-brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood-brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood-brain barrier function in the fetus. Blood-brain barrier function was quantified with the blood-to-brain transfer constant (K(i)) and tight junction proteins by Western immunoblot in fetal sheep at 127 days of gestation without ischemia, and 4, 24, or 48 h after ischemia. The largest increase in K(i) (P<0.05) was 4 h after ischemia. Occludin and claudin-5 expressions decreased at 4 h, but returned toward control levels 24 and 48 h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between K(i) and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood-brain barrier function after ischemia. We conclude that impaired blood-brain barrier function is an important component of hypoxic-ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (K(i)) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4 h after ischemia and blood-brain barrier function improves early after injury because the blood-brain barrier is less permeable 24 and 48 than 4 h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood-brain barrier permeability after ischemia.
authors.affiliation: Department of Pediatrics, The Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI 02905, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: S W
authors.initials: SW
authors.lastname: Threlkeld
authors.forename: E E
authors.initials: EE
authors.lastname: Cummings
authors.forename: I
authors.initials: I
authors.lastname: Juan
authors.forename: O
authors.initials: O
authors.lastname: Makeyev
authors.forename: W G
authors.initials: WG
authors.lastname: Besio
authors.forename: J
authors.initials: J
authors.lastname: Gaitanis
authors.forename: W A
authors.initials: WA
authors.lastname: Banks
authors.forename: G B
authors.initials: GB
authors.lastname: Sadowska
authors.forename: B S
authors.initials: BS
authors.lastname: Stonestreet
mesh_terms: D000465:Algorithms; D000621:Aminoisobutyric Acids; D000818:Animals; D001810:Blood Volume / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D015153:Blotting, Western; D001921:Brain / Q000196:embryology; D002545:Brain Ischemia / Q000503:physiopathology; D002339:Carotid Arteries / Q000502:physiology; D062445:Claudin-1 / Q000096:biosynthesis; D062507:Claudin-5 / Q000096:biosynthesis; D003720:Densitometry; D004569:Electroencephalography; D004912:Erythrocytes / Q000502:physiology; D005260:Female; D005333:Fetus / Q000502:physiology*; D062793:Occludin / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000503:physiopathology*; D012756:Sheep; D013667:Technetium; D062725:Tight Junction Proteins / Q000096:biosynthesis*; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D000621:Aminoisobutyric Acids; D062445:Claudin-1; D062507:Claudin-5; D062793:Occludin; D062725:Tight Junction Proteins; D013667:Technetium