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 reprodu cible model of HVOD, Rats gavaged with monocrotaline, 160 mg/kg, were kille d between days 1 and 10, Sections were evaluated by light microscopy with a standardized scoring system, by immunoperoxidase staining with ED-1 (monoc ytes, macrophages) and ED-2 (Kupffer cells) antibodies, and by transmission (TEM) and scanning electron microscopy (SEM). On days 1 and 2, the earlies t manifestations were progressive injury to the sinusoidal wall with loss o f sinusoidal lining cells, sinusoidal hemorrhage, and mild damage to centra l vein (CV) endothelium. On days 3 through 5 ("early HVOD"), there was cent rilobular coagulative necrosis, severe injury to sinusoids, severe sinusoid al hemorrhage, and severe CV endothelial damage; inflammation with ED-1-pos itive cells was most marked on these days. Days 6 and 7 ("late HVOD") were characterized by subendothelial and advential fibrosis of CVs, damage of th e CV endothelium with subendothelial hemorrhage, and some restoration of th e sinusoidal wall. Between days 8 and 10, sections showed interindividual v ariation ranging from mild, residual fibrosis to severe, late HVOD. From da ys 1 through 10, ED-2-positive cells were decreased in number, and the numb er 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 th e lobule and CVs is a result of recruitment of monocytes, whereas Kupffer c ells are decreased in number.