Cellular distribution of thrombomodulin as an early marker for warm ischemic liver injury in porcine liver transplantation: protective effect of prostaglandin I2 analogue and tauroursodeoxycholic acid.
BACKGROUND
Warm ischemia of the graft from non-heart-beating donors is considered a risk factor for posttransplant graft dysfunction. The early administration of cytoprotective agents may help improve graft dysfunction.


METHODS
Four groups of 10 pigs each underwent orthotopic liver transplantation. Prostaglandin I2 analogue, OP-41483, was administered intraportally 30 min before warm ischemic insult in donors and after reperfusion in recipients in one group. In the other study group, additional intravenous tauroursodeoxycholic acid (TUDC) was given before the warm ischemic insult in donors and after reperfusion, then maintained continuously until postoperative day (POD) 7.


RESULTS
Exposure of liver grafts to warm ischemia resulted in severe congestion with the disappearance of thrombomodulin (Tm) from the sinusoidal endothelial cells (SECs) and smooth muscle cells (SMCs) around biliary epithelial cells (BEpCs) 2 hr after reperfusion, followed by positive immunoreactivity of Tm in BEpCs with hyperbilirubinemia, which was related to high mortality. Combined administration of OP-41483 and TUDC had a protective effect, demonstrated by sustained immunoreactivity of Tm from SECs and SMCs until POD 7, without that reactivity in BEpCs. This was associated with reduced congestion and hyperbilirubinemia, similar to the control group not subjected to warm ischemia.


CONCLUSIONS
These findings suggest that negative immunoreactivity of Tm in SECs and SMCs surrounding BEpCs and positive in BEpCs may be an early marker for ischemic liver injury, and that OP-41483 and TUDC may protect against the microcirculatory and biliary derangement.
Ejiri
S
S
First Department of Surgery, Shiga University of Medical Science, Otsu-city, Japan.
Eguchi
Y
Y
Kishida
A
A
Ishigami
F
F
Kurumi
Y
Y
Tani
T
T
Kodama
M
M
D000818:Animals; D001652:Bile Ducts / Q000737:chemistry; D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000032:analysis*; D004396:Coloring Agents; D004801:Eosine Yellowish-(YS); D005456:Fluorescent Dyes; D006416:Hematoxylin; D006358:Hot Temperature; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry / Q000166:cytology*; D016031:Liver Transplantation / Q000401:mortality; D010477:Perfusion / Q000379:methods; D015427:Reperfusion Injury / Q000378:metabolism*; D015996:Survival Rate; D013552:Swine; D018180:Thrombomodulin / Q000032:analysis*
D015415:Biomarkers; D004396:Coloring Agents; D005456:Fluorescent Dyes; D018180:Thrombomodulin; D001663:Bilirubin; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin