Altered expression of zonula occludens-2 precedes increased blood-brain barrier permeability in a murine model of fulminant hepatic failure.
Brain edema secondary to increased blood-brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.
Shimojima
Naoki
N
Department of Transplantation, Division of Transplant Surgery, Mayo Clinic College of Medicine, Jacksonville, FL 32216, USA.
Eckman
Christopher B
CB
McKinney
Michael
M
Sevlever
Daniel
D
Yamamoto
Satoshi
S
Lin
Wenlang
W
Dickson
Dennis W
DW
Nguyen
Justin H
JH
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000098:blood supply; D004195:Disease Models, Animal; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D062827:Zonula Occludens-2 Protein
D008565:Membrane Proteins; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein