Elevated levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity

Inês Palmela, Filipa L. Cardoso, Michael Bernas, Leonor Correia, Ana R. Vaz, Rui F.M. Silva, Adelaide Fernandes, Kwang S. Kim, Dora Brites, Maria A. Brito

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The pathogenesis of encephalopathy by unconjugated bilirubin (UCB) seems to involve the passage of high levels of the pigment across the blood-brain barrier (BBB) and the consequent damage of neuronal cells. However, it remains to be clarified if and how the disruption of BBB occurs by UCB. We used confluent monolayers of human brain microvascular endothelial cells (HBMEC) to explore the sequence of events produced by UCB. A cell line and primary cultures of HBMEC were exposed to 50 or 100 ìM UCB, in the presence of 100 ìM human serum albumin, to mimic moderate and severe jaundice, for 1-72 h. UCB caused loss of cell viability in a concentration-dependent manner. UCB inhibited the secretion of interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and vascular endothelial growth factor at early time points, but enhanced their secretion later on. Upregulation of mRNA expression, particularly by 100 ìM UCB, preceded cytokine secretion. Other early events include the disruption of glutathione homeostasis and the increase in endothelial nitric oxide synthase expression followed by nitrite production. Prolonged exposure to UCB upregulated the expression of ß-catenin and caveolin-1. In conclusion, elevated concentrations of UCB affect the integrity of HBMEC monolayers mediated by oxidative stress and cytokine release. UCB also induced increased expression of caveolin-1, which has been associated with BBB breakdown, and β-catenin, probably as an attempt to circumvent that impairment. These findings provide a basis for target-directed therapy against brain endothelial injury caused by UCB.

Original languageEnglish (US)
Pages (from-to)153-169
Number of pages17
JournalCurrent Neurovascular Research
Volume8
Issue number2
DOIs
StatePublished - May 1 2011

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Keywords

  • Blood-brain barrier
  • Caveolin-1
  • Cytokines
  • Endothelial cells
  • Oxidative stress
  • Unconjugated bilirubin
  • Vascular endothelial growth factor
  • β-catenin

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

Palmela, I., Cardoso, F. L., Bernas, M., Correia, L., Vaz, A. R., Silva, R. F. M., Fernandes, A., Kim, K. S., Brites, D., & Brito, M. A. (2011). Elevated levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity. Current Neurovascular Research, 8(2), 153-169. https://doi.org/10.2174/156720211795495358