J. Bendahan et al., THE EFFECT OF ADMINISTRATION OF FK506 ON DELAYED REGENERATION IN FLUSHED PARTIALLY HEPATECTOMIZED LIVERS, Transplantation, 57(5), 1994, pp. 655-658
It has been shown previously that liver regeneration after partial hep
atectomy in rats is delayed if the liver is subjected to either concur
rent ischaemia, flushing with cold solution, or grafting. We have show
n recently that treatment with CsA preoperatively overcomes the suppre
ssive effect of flushing and returns the regenerative response to a no
rmal time scale. The present study was designed to investigate whether
ad ministration of FK506 would also return the observed delayed regen
erative response to normal. Long-Evans rats weighing 250-350 g were su
bjected to standard 68% partial hepatectomy. Group 1 had no further tr
eatment; in group 2, the liver remnant was flushed with 10 ml cold (4
degrees C) Ringers lactate solution, and in group 3, FK506 (1 mg/kg/da
y) was administered by intramuscular injection for 3 days before the p
artial hepatectomy and flushing as in group 2; a final dose was given
after completion of the procedures. Animals were killed in sets of 6 p
er group at 4, 24, 48, 72, and 96 hr after surgery and blood samples w
ere taken for measurement of plasma aspartate aminotransferase. Liver
biopsies were analyzed for measurement of thymidine kinase and ornithi
ne decarboxylase activity and for counting of mitotic figures. While t
he highest recorded thymidine kinase activity occurred in group 1 at 2
4 hr, this was delayed to 48 hr in both groups 2 and 3 and counts rema
ined high up to 96 hr in group 3. Mitotic indices were only significan
tly elevated (compared with group 1 at 96 hr), while ornithine decarbo
xylase activity did not correlate with these changes being significant
ly lower than in groups 2 and 3 at 4 hr and in group 3 also at 24 hr.
Plasma aspartate aminotransferase was also significantly higher in gro
up 3. It is concluded that the administration of FK506 preoperatively
to rats subjected to partial hepatectomy and flushing did not restore
the delayed regenerative response to normal but enhanced the response
(as measured by thymidine kinase but not by mitotic indices) which com
menced at 48 hr and was still present at 96 hr.