Sinusoidal obstruction syndrome (veno-occlusive disease) in the rat is prevented by matrix metalloproteinase inhibition.
OBJECTIVE
The mechanical origins of the obstruction in sinusoidal obstruction syndrome are initiated by dehiscence of sinusoidal endothelial cells from the space of Disse. The biochemical changes that permit the dehiscence of the sinusoidal endothelial cells were investigated.


METHODS
In vitro and in vivo studies examined changes induced by monocrotaline, a pyrrolizidine alkaloid that induces sinusoidal obstruction syndrome in both humans and experimental animals.


RESULTS
In the monocrotaline-induced rat model of sinusoidal obstruction syndrome, there was an early increase of matrix metalloproteinase-9 and a later, lower-magnitude increase of matrix metalloproteinase-2 in the liver. In vitro studies of sinusoidal endothelial cells, hepatocytes, stellate cells, and Kupffer cells showed that sinusoidal endothelial cells are the major source of both basal and monocrotaline-induced matrix metalloproteinase-9/matrix metalloproteinase-2 activity. Monocrotaline caused depolymerization of F-actin in sinusoidal endothelial cells, and blocking of F-actin depolymerization prevented the increase in matrix metalloproteinase activity. Administration of matrix metalloproteinase inhibitors prevented the signs and histological changes associated with sinusoidal obstruction syndrome.


CONCLUSIONS
Monocrotaline causes depolymerization of F-actin in sinusoidal endothelial cells, which leads to increased expression of metalloproteinase-9 and matrix metalloproteinase-2 by sinusoidal endothelial cells. Inhibition of matrix metalloproteinase-9 and matrix metalloproteinase-2 prevents the development of sinusoidal obstruction syndrome, establishing that matrix metalloproteinase inhibitors may be a therapeutically viable strategy for prevention.
Deleve
Laurie D
LD
Division of Gastrointestinal and Liver Disease, University of Southern California Keck School of Medicine, Los angeles, California 90033, USA. deleve@usc.edu
Wang
Xiangdong
X
Tsai
Jeffrey
J
Kanel
Gary
G
Strasberg
Steven
S
Tokes
Zoltan A
ZA
D000199:Actins / Q000737:chemistry; D000818:Animals; D006504:Hepatic Veno-Occlusive Disease / Q000517:prevention & control*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D016686:Monocrotaline; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000199:Actins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D016686:Monocrotaline