Liver Pathology and Cell Proliferation After Calcineurin Inhibitors and Antiproliferative Drugs Following Partial Hepatectomy in Rats H. Kirimlioglu, V. Kirimlioglu, S. Yilmaz, S. Coban, E. Turkmen, and C. Ara ABSTRACT Immunosuppressants are the cornerstones of treatment after solid organ transplantation. This study investigated the pathology and cell proliferation following partial hepatectomy (PH) in rats undergoing immunosuppressive treatment. After 1 day, all rats were subjected to 70% PH. Groups A and B (n = 10) received calcineurin inhibitors subcutaneously: either FK506 or cyclosporine (CyA). Groups C and D (n = 10) received antiproliferative drugs: either mycophenolate mofetil (MMF) or sirolimus (SRL) by gavage. A control group (n = 5) received 1 mL of tap water daily. On postoperative day 2, all rats were sacrificed to obtain liver tissue for pathologic examination. Using immunohistochemistry we separately examined the hepatectomy surface and the liver parenchyma. In the parenchyma, the Ki-67 indices were higher in the CyA and FK506 groups and lower in the SRL and MMF groups compared with controls (P  .01). CyA had the highest and MMF the lowest values. On the hepatectomy surface, Ki-67 indices and TGF-alpha expressions were higher in the CyA group and lower in the SRL and MMF groups compared with the control group (P  .01). Slightly higher values in the FK506 group were not significantly different compared with the control group (P  .05). All groups other than FK506 showed prominent cholangiolar epithelial phenotypes compared with the control group. In the CyA and SRL groups, the number of cholangiolar cells was higher (P  .01), and in the MMF group lower than in the control group (P  .01). Among all groups, SRL had the highest values. I MMUNOSUPPRESSANTS are cornerstones of treat- ment following solid organ transplantation. Today split liver grafts are no longer reserved for children but are employed with increasing frequency in adults. The liver shows a high capacity for regeneration after partial hepa- tectomy (PH). 1,2 Following PH, cell proliferation does not ensue at the level of the cut; new lobes do not develop to take the place of those removed. 2 There is hyperplasia of the remaining lobes which reaches 50% at 16 to 24 hours after 70.6% PH in the rat. 2 Over the last years this topic has been the subject of extensive animal research which sug- gests the roles of a variety of factors: Follistatin, 3 interferon gamma, 4 and immunosuppressants. 1,5 Our previous study showed that the onset of liver regeneration after PH is inhibited by the use of new immunosuppressive drugs. 1 MATERIALS AND METHODS Male Swiss albino rats weighing about 200 to 250 g were obtained from Fırat University, Animal Laboratory, Elazig, Turkey. All experiments were performed in accordance with the guidelines for Animal Research from the National Institutes of Health and were approved by our Committee on Animal Research. The animals were housed in stainless-steel cages under controlled temperature and humidity conditions and in a quiet room with a 12/12-hour light/dark cycle. Rats were maintained on a standard laboratory diet with tap water ad libitum throughout the experiment, except for an overnight fast before surgery. All surgical procedures were performed under sterile conditions. The animals underwent PH according to the method of Higgins and Anderson, 2 while sedated with intraperitoneal ketamine (50 mg/kg) and xylazine HCl (10 mg/kg) anesthesia. Briefly, for a 70% hepatectomy the median lobe, left lateral lobe, and right lateral lobe were resected. All animals were treated with 100 mg/kg mezlocillin (Baypen, Bayer, Istanbul, Turkey) by intramuscular injection once at the time of surgery. From the Departments of Pathology (H.K., E.T.) and General Surgery (V.K., S.Y., S.C., C.A.), Inonu University, School of Medicine, Malatya, Turkey. Address reprint requests to Vedat Kirimlioglu, MD, Depart- ment of General Surgery, Inonu University, Turgut Ozal Medical Center, Malatya, Turkey. E-mail: vkirimlioglu@inonu.edu.tr 0041-1345/06/$–see front matter © 2006 by Elsevier Inc. All rights reserved. doi:10.1016/j.transproceed.2005.12.097 360 Park Avenue South, New York, NY 10010-1710 622 Transplantation Proceedings, 38, 622– 626 (2006)