Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining

Inês Palmela, Hiroyuki Sasaki, Filipa L. Cardoso, Miguel Moutinho, Kwang Sik Kim, Dora Brites, Maria A. Brito

Research output: Contribution to journalArticle

Abstract

In neonatal jaundice, high levels of unconjugated bilirubin (UCB) may induce neurological dysfunction (BIND). Recently, it was observed that UCB induces alterations on brain microvasculature, which may facilitate its entrance into the brain, but little is known about the steps involved. To evaluate if UCB damages the integrity of human brain microvascular endothelial cells (HBMECs), we used 50 or 100 μM UCB plus human serum albumin, to mimic the neuropathological conditions where levels of UCB free species correspond to moderate and severe neonatal jaundice, respectively. Our results point to a biphasic response of HBMEC to UCB depending on time of exposure. The early response includes increased number of caveolae and caveolin-1 expression, as well as upregulation of vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) with no alterations of the paracellular permeability. In contrast, effects by sustained hyperbilirubinemia are the reduction in zonula occludens (ZO)-1 and β-catenin levels and thus of tight junctions (TJ) strands and cell-to-cell contacts. In addition, reduction of the transendothelial electrical resistance (TEER) and increased paracellular permeability are observed, revealing loss of the barrier properties. The 72 h of HBMEC exposure to UCB triggers a cell response to the stressful stimulus evidenced by increased autophagy. In this later condition, the UCB intracellular content and the detachment of both viable and non-viable cells are increased. These findings contribute to understand why the duration of hyperbilirubinemia is considered one of the risk factors of BIND. Indeed, facilitated brain entrance of the free UCB species will favor its parenchymal accumulation and neurological dysfunction.

Original languageEnglish (US)
JournalFrontiers in Cellular Neuroscience
Issue numberMAY 2012
DOIs
StatePublished - May 10 2012

Fingerprint

Blood-Brain Barrier
Bilirubin
Brain
Neonatal Jaundice
Hyperbilirubinemia
Endothelial Cells
Tight Junctions
Permeability
Caveolin 1
Caveolae
Catenins
Vascular Endothelial Growth Factor Receptor-2
Autophagy
Microvessels
Electric Impedance
Serum Albumin
Up-Regulation

Keywords

  • Blood-brain barrier
  • Caveolae
  • Endothelial cells
  • Integrity
  • Intercellular junctions
  • Unconjugated bilirubin
  • VEGF
  • VEGFR-2

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining. / Palmela, Inês; Sasaki, Hiroyuki; Cardoso, Filipa L.; Moutinho, Miguel; Kim, Kwang Sik; Brites, Dora; Brito, Maria A.

In: Frontiers in Cellular Neuroscience, No. MAY 2012, 10.05.2012.

Research output: Contribution to journalArticle

Palmela, Inês ; Sasaki, Hiroyuki ; Cardoso, Filipa L. ; Moutinho, Miguel ; Kim, Kwang Sik ; Brites, Dora ; Brito, Maria A. / Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining. In: Frontiers in Cellular Neuroscience. 2012 ; No. MAY 2012.
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