Kahn, D

Lai, HS

Makowka, L

Romovacek, H

Starzl, TE

Van Thiel, D

PubMed

D-Scholarship@Pitt

------------ .. -K--------~----~ Cyclosporine A Augments the Regenerative Response After Partial Hepatectomy in the Rat D. Kahn, H. S. Lai, H. Romovacek, L. Makowka, D. Van Thiel, and T.E. Starzl I N J U R Y to the liver results in a regenera-tive response that is characterized by pro-liferation of both parenchymal and littoral cells. During orthotopic transplantation of the liver, the liver may be injured by ischemia during the harvesting procedure and by rejec-tion in the posttransplant period. Cyclosporine A (CsA), a powerful immunosuppressive agent, is used routinely after orthotopic liver transplantation, and it thus seemed appropri-ate and important to study the effect of CsA on hepatic regeneration. MATERIALS AND METHODS Male Wistar rats weighing 250 to 300 g were randomly assigned to three groups and treated as follows: Group r Days 1-7, CsA in olive oil 25 mg/kg orally; day 8. CsA in saline 5 mg/kg intravenously (IV) followed by partial hepatectomy (PH). Group If. Days 1-7, olive oil vehicle orally; day 8, saline IV followed by PH. Group III. Days 1-7, CsA in olive oil 25 mg/kg orally; day 8, CsA in saline 5 mg/kg IV followed by sham PH. Standard 70% PH' and sham PH were carried out between 8:00 AM and 11.00 AM to avoid the effect of diurnal variation. All surgical procedures were performed under ether anesthesia. Rats were killed at 6, 24, and 48 hours after partial hepatectomy. The remnant livers were removed and weighed, and used to measure hepatic thymidine kinase (TK) and ornithine decarboxylase (ODC) activities. as From the Departments 0/ Surgery and Medicine. iDni~ers;ty Hea/th Center 0/ PiIlsburgh. UniH'rsity 0/ Pillsburgh. and the Veterans Administration Medical Center. Pittsburgh. Supported by research grants from the Veterans Administration and Project Grant No. AM 29961/rom the .... ationa/lnstitutes 0/ Health. Bt'lhesda. MD. Address reprint requests to Dr D. Kahn. Department 0/ Surgery. 3601 Fi/th Ave. Fo/k Clinic 4 West. PillS-burgh. PA 15213. ~f 988 by Grune & Stratton. Inc. 0041 -I 345/88/2003-3161 $03.00/0 described previously.2.J All results are presented mean:!: SEM and compared using analysis of varia U • 1ICt. RESULTS The liver weight/body weight (LW law) ratio, shown in Table I, remained unchanged after sham PH. However, there was a stead increase in L W /BW ratio after PH and by T~ hours was almost the same as control values The L W /BW ratios were similar after PH i~ rats pretreated with CsA and those pretreated with the vehicle. Preoperative ODC activity (Table 2) was significantly higher in rats pretreated with CsA (P < .01). At six hours, levels of ODe activity were significantly elevated in all three groups (P < .01), with the levels of actiVity being highest in rats treated with CsA and PH. The ODC activity returned to normal at 24 hours in rats subjected to sham PH, but was still significantly elevated after PH; again, levels were highest in rats treated with CsA and PH. The changes in TK activity are shown in Table 3. Preoperative levels of TK activity were also significantly higher in rats pre-treated with CsA (P < .01). Levels of TK activity were not elevated at 24 hours after sham PH and were in fact lower than preoper-ative values. There was a significant increase in TK activity at 24 hours after PH. with levels being significantly higher in rats pre-treated with CsA (P < .05). Table 1. liver Weight/Body Weight Ratios (x 10') in Rata Treated With CIA and PH (Group I), Vehicle and PH (Group II), and CIA and Sham PH (Group III) (M.an:< SEM) 6h 24 h 48h dr~1 97:< 6 117 % 4 168 % 9 dr~1f 105 % 5 146 % 14 147 % 21 dr~1ff 262 % 10 269 :!: 4 252 ± 5 850 Transplantation Proceedings. Vol XX. No 3. Suppl 3 (June). 1988: pp 850-852 febls 2 Treated \ (Grol ------",..,perot''''' eh 21h "h ---Preope treated \\ treated \\ a signific ciated WI small but The injur pretreate The c;.. response studied e tation of viabl ~ a patier,ts liver trar ·in a nun-injury dL attack b posttran liver. Cs presive and its, thus see CsA on The t response Table 3. Pre 6h 24 48 nse 'cnlecj &I r . • vanance. -W/BW) nchanged a steady tnd by 72 )1 values. er PH in retreated e 2) Was ted with of ODe all three activity :::-sA and ormal at PH, but ter PH; ted witb hown in activity ats pre-; of TK l rs after 'Jreoper-Increase H. with ats pre-.10") In ,cl. and pHI) up III " 10 ~ 4 ! 5 350-852 csA AND HEPATIC REGENERATION Table 2. ODe Activity (cpm/mg Proteinl in Reta Treated With CIA and PH (Group II. Vehicle and PH (Group II), and CeA and Shem PH (Group 1111 (Mean j: SEMI -Group I GrO<4)II GrO<4)III -. 726 " 18 546" 11 726 % 18 p,.operauve en 4.984 % 337 3.096 % 785 2.573 " 238 2'" 3.619 " 631 2,068 % 711 685" 18 48n 2.319 % 242 2,557 " 128 741 :t 28 ---Preoperative li~er function tests ift- rats pre-treated with CsA were similar to those pre-treated with the vehicle (Table 4). There was a significant increase in SGOT levels asso-ciated with the injury of the PH, and also a small but significant increase after sham PH. The injury pattern after PH was less in rats pretreated with CsA. DISCUSSION The capacity of the liver to regenerate in response to various forms of injury has been studied extensively. In recent years transplan-tation of the liver has become accepted as a viable alternative in the management of patients with end-stage liver disease. During liver transplantation the liver may be injured ·in a number of ways, including the ischemic injury during harvesting and the immunologic attack by the host. Certain drugs used in the posttransplant period may also be toxic to the liver. CsA is used routinely in the immunosup-presive regimen after liver transplantation and its side-effects include hepatotoxicity. It thus seemed important to study the effect of CsA on hepatic regeneration. The effect of CsA on the regenerative response may also be relevant in certain cases 851 Table 4. Serum SGOT levels (Mean :t SEMI in Rau Treated With C.A and PH (Group I). Vehicle and PH (Group II), end CeA and Sham PH (Group 1111 GrO<4)I GrO<4)II GrO<4) III Preoperative 83 l: 18 85:1: 8 83:1: 18 6h 1,520:1: 407 1.146j:167 147 j: 15 24h 1.399 j: 78 2,467 j: 663 110:1: 2 48 h 543:1: 100 1,976 :I: 800 106 :I: 8 of pediatric liver transplantation where, because of the critical shortage of suitable pediatric donors, many centers have resorted to using reduced-size adult liver grafts, A normal regenerative response may be neces-sary for the successful outcome of these grafts. ODC is the rate-limiting enzyme in poly-amine synthesis, and increased polyamine synthesis is thought to playa critical role in the stimulation of hepatic regeneration after partial hepatectomy, In addition, regenera-tion of the liver involves an increase in DNA synthesis in the liver, which requires an induc-tion of hepatic TK activity. Thus, these two enzymes were used as indices of liver regener-ation, Both TK activity and ODC activity were significantly higher after partial hepa-tectomy in rats pretreated with CsA, Thus, there appears to be increased hepatic regeneration after partial hepatectomy in rats treated with CsA. CsA is known to be hepato-toxic and this may account for the greater regenerative response. However, preoperative liver function tests in the rats pretreated with CsA were the same as control values. On the other hand, the injury may be subclinical and not detected by routine tests of liver function. It may be that CsA induces both ODC and Table 3, TK Activity (dpm/mg Protein) in Rats Treated With CIA and PH (Group I), Vehicle and PH (Group II). and CIA and Sham PH (Group III) (Mean :I: SEM) GrO<4)I Group II GrO<4) III Preoperative 4.364 :I: 847 1 ,246 ~ 219 4,364 ~ 847 6h 4,403 j: 1.242 581 ~ 90 1,525:1: 101 24 h 16.777:1: 581 11, I 10 :I: 1,269 1.098 ~ 76 48 h 10.736" 640 12,623 j: 1.457 3,921 :I: 749 " ~" _._--_._-------852 TK. This would account for the significantly higher preoperative levels of activity of both enzymes in rats pretreated with CsA and would explain the significant elevation in ODC at six hours after sham operation. The data presented in this study demon-strate that CsA at the dosage used did not adversely affect hepatic regeneration after KAHN ET At partial hepatectomy in rats and a t . c Uall" resulted 10 a greater regenerative res"" I l;'Vnse. REFERENCES I. Higgins GM. Anderson RM: Arch Palhol 12. 1931 .184. 2. Kahn D, Stadlet J, Terblanche J, el al: GUt enterol 79:907. 1980 ~ 3. McGowan JA, Fausto N: Biochem J 170:120,197, Effects of Cy· L.E THE FUNGAL met (CsA) has contrib . the results in organ t In f' mechanism 0 actl~n .(udied but the precIse s . . t a cellular level IS stl a . I effects of CsA, malO ) liver. has limited its use noSupprcssive propertl chamisms for the t unknown, and it is L parent compound or responsible for the ph. effects. Rats receiving CsA kg/d) displayed incre.a rubin, alanine transmlr phatase, while the 1 decreased. I I Light mi revealed a moderate L predominantly in the Electron microscopic dilatation of the endo' an increased number uoles. 12·\) No proliferat reticulum could be ( endoplasmic membra, normal numbers of Decreased amount ane P-450 and NADPH-\, was reported after Cs:\ treatment to rats deere somal ,a-oxidation of I activity of catalase a' lated peroxisomes. ( been reported to cour simultaneouslyadmin In addition, CsA treat impair the production cose tolerance in ral maintained in culture (I Jlg/mL) displayed biosynthesis and deere Transplanta/lon Proceedings ~K ,', '. . '. . ,- . -. ' Dr~ , ~ 

Cyclosporine A augments the regenerative response after partial hepatectomy in the rat.

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Cyclosporine A augments the regenerative response after partial hepatectomy in the rat.

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