Factor VII transcription correlates with hepatocyte proliferation and hepatocyte growth factor expression in a rodent extrahepatic portal vein obstruction model.
BACKGROUND
Extrahepatic portal vein obstruction (EHPVO) is clinically associated with decreased liver-dependent coagulation factors and smaller than normal liver volumes. We developed a rodent EHPVO model to describe changes in coagulation factor regulation and liver homeostasis.


METHODS
Fifteen rats underwent controlled narrowing of the portal vein (PV) at the hilum, and 15 underwent sham operations. Three animals from each group were sacrificed at postoperative days (PODs) 1, 2, 4, 7, and 21. Their livers were studied for apoptosis, proliferation, and hepatocyte growth factor (HGF) expression using terminal transferase dUTP nick end labeling (TUNEL) assays, Ki-67, and hepatocyte growth factor antibody. Liver total RNA was harvested for reverse transcriptase-polymerase chain reaction (RT-PCR), using primers for factors V, VII, VIII, X, protein C, and antithrombin. Appropriate statistical analysis was applied.


RESULTS
Ligation of the portal vein in the experimental group resulted in a 59+/-17% (mean +/- standard deviation) decrease in distal portal vein diameter. Proportional body weight was equivalent in both groups, but spleen weight was higher in the experimental group at PODs 4, 7, 21, and liver weight was higher at POD 7 (p < 0.05). The percentage of apoptotic cells in the experimental group increased from that of the control group at POD 4 (p < 0.05). The percentages of proliferating cells, HGF expression, and factor VII transcription in the experimental group were lower than those of controls at POD 2 (p < 0.05) but higher at POD 7 (p < 0.05). Ki-67/TUNEL double staining showed no grouping of apoptotic and proliferating cells. Factor V transcription in the experimental group was increased compared with that in controls at POD 2 (p < 0.05). Transcription of factors VIII, X, protein C, and antithrombin was unchanged.


CONCLUSIONS
Our model demonstrated an early increase in hepatocyte apoptosis, impairment of factor VII transcription, and decrease in proliferative indices. These data support the hypothesis that EHPVO disrupts hepatic homeostasis and leads to dysregulation of coagulation factor synthesis.
Department of Surgery, Children's Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Bill
B
Chiu
Hector
H
Melin-Aldana
Srikumar
S
Pillai
Fei
F
Chu
Riccardo A
RA
Superina
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005167:Factor VII / Q000235:genetics*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D022781:Hepatocytes / Q000166:cytology*; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014652:Vascular Diseases / Q000235:genetics* / Q000378:metabolism*
D017228:Hepatocyte Growth Factor; D005167:Factor VII