Characterization of a reproducible rat model of hepatic veno-occlusive disease.
Lack of a reproducible animal model has hampered progress in understanding hepatic veno-occlusive disease (HVOD). This article characterizes a reproducible model of HVOD. Rats gavaged with monocrotaline, 160 mg/kg, were killed between days 1 and 10. Sections were evaluated by light microscopy with a standardized scoring system, by immunoperoxidase staining with ED-1 (monocytes, macrophages) and ED-2 (Kupffer cells) antibodies, and by transmission (TEM) and scanning electron microscopy (SEM). On days 1 and 2, the earliest manifestations were progressive injury to the sinusoidal wall with loss of sinusoidal lining cells, sinusoidal hemorrhage, and mild damage to central vein (CV) endothelium. On days 3 through 5 ("early HVOD"), there was centrilobular coagulative necrosis, severe injury to sinusoids, severe sinusoidal hemorrhage, and severe CV endothelial damage; inflammation with ED-1-positive cells was most marked on these days. Days 6 and 7 ("late HVOD") were characterized by subendothelial and advential fibrosis of CVs, damage of the CV endothelium with subendothelial hemorrhage, and some restoration of the sinusoidal wall. Between days 8 and 10, sections showed interindividual variation ranging from mild, residual fibrosis to severe, late HVOD. From days 1 through 10, ED-2-positive cells were decreased in number, and the number of ED-1-positive cells was increased. Sinusoidal damage is the earliest change in HVOD. Coagulative necrosis follows sinusoidal injury and resolves with improvement in sinusoidal endothelial cell (SEC) morphology. Moderate-to-severe CV fibrosis occurs after reappearance of sinusoidal lining cells and resolution of hepatocyte necrosis. The inflammatory response within the lobule and CVs is a result of recruitment of monocytes, whereas Kupffer cells are decreased in number.
DeLeve
L D
LD
Division of Gastrointestinal and Liver Diseases, USC School of Medicine, Los Angeles, CA, USAdeleve@hsc.usc.edu
McCuskey
R S
RS
Wang
X
X
Hu
L
L
McCuskey
M K
MK
Epstein
R B
RB
Kanel
G C
GC
D000818:Animals; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D006470:Hemorrhage; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D007249:Inflammation; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D009336:Necrosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors
D016686:Monocrotaline