Mammalian liver is known to contain cytosolic receptors for both estrogens and androgens. Furthermore, certain mammalian hepatic functions are known to display a sexual dimorphism. However, in clinical liver transplantation, the sex of the donor is not taken into consideration in selection of the donor. In this study, the effect of liver transplantation on the estrogen and androgen receptor content of the liver was determined. Adult male and female rats were subjected to orthotopic liver transplantation, using donors from both the same and the opposite sex as the recipient. The animals were killed on the tenth postoperative day, and the livers were assayed to determine their cytosolic estrogen and androgen receptor content. Transplantation of a liver from a male donor into a male recipient, from a male donor into female recipient and from a female donor into a male recipient produced similar changes in the number of cytosolic estrogen and androgen receptors in hepatic cytosol. In all three situations, the estrogen receptor content in the cytosol of the transplanted liver was the same as that found in an unoperated male liver, and the cytosolic content of the androgen receptor was the same as that of an unoperated female liver. After transplantation of the liver from a female donor into a female recipient, the estrogen and androgen receptor content in the cytosol of the transplanted liver was the same as that of an unoperated female.(ABSTRACT TRUNCATED AT 250 WORDS)

Orthotopic liver transplantation was performed in 60 recipient rats weighing 200 to 250 gm. Sixty rats of the same strain were used as liver donors, 30 weighing 100 to 140 gm (small for size) and the other 30 weighing 200 to 250 gm (same size). After 1, 2, 3, 4, 7 and 14 days (n = 5 each) DNA synthesis, nuclear thymidine labeling and mitoses were increased in both the small-for-size and samesize groups, but significantly more in the former. These changes were maximal after 48 to 72 hr, similar to but later than the well-known regeneration response after partial hepatectomy, which peaks at 24 hr in rats. Indirect indexes of regeneration of the transplanted livers also were measured: plasma or serum ornithine decarboxylase; insulin and glucagon serum levels; estradiol and testosterone serum levels (and their nuclear and cytosolic receptors); and transforming growth factor-β, c-Haras and c-jun mRNA expressions. With the small-for-size transplantation, these followed the same delayed pattern as the direct regeneration parameters. The small livers gradually increased in size over the course of 1 to 2 wk and achieved a volume equal to that of the liver originally present in the recipient. In contrast, no significant liver weight gain occurred in the transplanted livers from samesize donors despite the evidence of regeneration by direct indexes, but not by most of the surrogate parameters, including ornithine decarboxylase.It has previously been demonstrated, both in human beings (1) and in dogs (2), that a liver from a small donor transplanted into a larger recipient undergoes hypertrophic and hyperplastic changes that result in a progressive increase of liver volume, until the transplanted liver reaches the appropriate size for the recipient. In this study this process of liver growth was better characterized by examination of multiple parameters. These included the direct regeneration indexes of DNA synthesis, labeled nuclei and subsequent mitosis (3-5). Surrogate manifestations of regeneration also were monitored: systemic insulin and glucagon; circulating sex steroid hormones and their nuclear and cytosolic liver receptors (6-12); and the expression of transforming growth factor-β (TGF-β) mRNA (13,14), c-Ha-ras mRNA (15) and c-jun mRNA (16,17). These changes after transplantation of small-for-size livers were compared with those occurring after transplantation of size-matched livers.Address reprint requests to: Antonio Francavilla, M.D., VA Hospital, University Drive C, Building 6, Pittsburgh, PA 15240. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2010 November 9. MATERIALS AND METHODS AnimalsMale Fischer rats (F-344) weighing 180 to 220 gm or 90 to 120 gm were purchased from Zivic Miller Laboratories (Zelienople, PA). All the animals were maintained in a temperature-and light-controlled room (light from 6:30 AM to 6:30 PM) for at least 1 wk before being used, after their body weight had reached the appropriate ranges. They received food and water ad libitum. Our inst...

Rat livers were preserved with the conventional use of UW solution for 30, 42, and 48 hr and compared with livers in which the vascular bed was expanded with an additional 10 to 60 ml UW/ 100 g liver. The extra UW, expressed as % liver weight, was entrapped during final portal infusion by tying off the supra-and infrahepatic inferior vena cava. A beneficial influence of the vascular expansion was most pronounced in the 40% group, with 10/10, 5/10, and 3/10 long-term survivors following transplantation after 30, 42, and 48 hr preservation versus 3/10 and 0/10 after 30 and 42 hr in the 0% controls. In separate experiments, surrogate indices of preservation quality following reperfusion explained this effect. The 40%-and, to a lesser extent, 20%-livers had higher and more uniformly distributed portal blood flow, better tissue oxygenation, smaller increases in postperfusion liver enzymes, higher adenine nucleotides and energy charge, and less histopathologic evidence of hemorrhage and congestion. Pressure changes in the vena cava fluid sump in additional experiments indicated that retrograde infusion of the trapped UW solution occurred in all of the 10-60% groups during the first 6 hr with stable pressures of 1.5 to 3 cm H 2 0 thereafter. Collectively, these data suggest that the much discussed selective vulnerability of the microvasculature of stored allografts is due in part (or principally) to its selective lack of long-term exposure to the UW solution, which drains out of the open vessels but not from the parenchyma. The potential clinical exploitation of this concept is discussed.Recent literature has emphasized microvascular injury as the principal limitation of static cold liver preservation (1-3). With these methods, the preservation solution does not thoroughly fill the microvasculature and remain there. With the hypothesis that microvasculature collapse during the preservation deprives the vessels of benefit from the preservation fluid and increases the resistance for the reperfusion blood flow, we tested a modification of the standard technique. In our experiment, different amounts of UW solution were infused into preserved rat livers, followed by occlusion of all vessels in order to trap the fluid within the vasculature at all levels. The results after orthotopic transplantation were compared with those using the conventional static preservation technique for various durations. MATERIALS AND METHODS AnimalsMale Lewis rats, weighing 225 to 300 g, were used for donors and recipients, housed in individual cages, and fed ad libitum until the night before the experiment. Operative proceduresOrthotopic rat liver transplantation was performed by the method of Kamada et al., without reconstruction of the hepatic artery (4). Donors were anesthetized by intraperitoneal injection of 50 mg/kg sodium pentobarbital. After ligation of the phrenic veins, the donor liver was NIH Public Access flushed with 5 ml of cold UW solution through a catheter inserted in the abdominal aorta. The organ was then removed, with...

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p < 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p < 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection. Keywords hepatic regeneration; portal hypertension; cirrhosis; liver growth; protal blood flow The origin and nature of the factors that control hepatic regeneration remain unresolved. Portal blood has been shown to be hepatotrophic as compared to peripheral blood. 1 However, controversy continues to surround the relative importance of the qualitative changes (hormonal factors) and the quantitative changes (blood flow parameters) in portal blood that occur after partial hepatectomy as they relate to the hepatic regeneration that occurs after a partial hepatic resection. 1-8 The pancreatic hormones, insulin and glucagon, have been shown to modulate, at least in part, the regenerative response that occurs after partial hepatectomy. 1-5 These data, however, do not negate an important role for hepatic blood flow, particularly portal venous blood flow, in the regulation of hepatic regeneration following partial hepatectomy. [6][7][8] The role of hepatic blood flow in modulating liver regeneration was first suggested by the observation that hepatic atrophy occurs after an Eck fistula (end-to-side portal caval shunt). 6 This hepatic atrophy was thought to be the result of a reduced hepatic blood flow,

For a decade, liver transplant recipients have been treated with cyclosporine, a drug with modest hepatotoxicity (1). Concern that CsA might inhibit hepatic regeneration or the ability of the transplanted liver to adjust its size to that of the recipient prompted studies by Makowka et al.(2) and others (3-5), which showed that regeneration actually was enhanced. A newer unrelated immunosuppressive agent, FK506, has the same properties (5). In addition, these 2 drugs have other actions that are collectively called hepatotrophic. The increase in hepatocyte replication that is caused by portacaval shunt in dogs is more than doubled by intrahepatic infusion of either of these drugs via the tied-off central portal vein, and the expected atrophy and organelle disruption is prevented (6,7). Direct experimentation in nude rats has ruled out immune modulation of lymphocytes and NK cells as an explanation (8).