Small-for-size liver transplanted into larger recipient: A model of hepatic regeneration

Abstract

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...

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Portomesenteric disconnection for small-for-size grafts in liver transplantation: Preclinical studies in pigs

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