First approaches for the transplantation of hepatocytes from Wistar rat preneoplastic livers into healthy recipients.

BACKGROUND: the shortage of donors of hepatocyte transplantation therapy led to the use of so-called marginal donors. Some donors may have a hepatic illnesses that is associated with hepatic preneoplasia with foci of altered hepatocytes (FAH). AIMS: to determine whether recipients developed FAH upon transplantation with hepatocytes from a preneoplastic liver and whether FAH progresses to a preneoplastic hepatocyte-derived tumor (PHDT), up to 60 days after transplantation. MATERIAL AND METHODS: male Wistar adult rats were used as donors and recipients. Donors underwent a 2-phase model of liver preneoplasia for hepatocyte isolation. Recipients underwent a partial two thirds hepatectomy and received 150,000 hepatocytes. Recipients were euthanized seven and 60 days after transplantation. The number of FAH per liver area, percentage of liver occupied by FAH, the hepatic enzymatic profile, the percentage of prothrombin time (PT), the proliferative index (PI) and liver morphology were analyzed. RESULTS: recipients developed few and very isolated FAH. No statistical differences were found between hepatic enzyme activities and PT. There were no differences between the groups with regard to the number of FAH per liver area and percentage of liver occupied by FAH after 60 days. The PI decreased on day 60 compared to day seven. No morphological alterations were found. CONCLUSIONS: recipients developed few FAH that did not increase in number or size, nor did they progress to PHDT and had normal plasma biochemical features and liver morphology up to 60 days post-transplant. Additional studies are needed to determine whether FAH development constitutes a risk for recipients while waiting for whole organ transplant.

Participation of 5-lipoxygenase and LTB4 in liver regeneration after partial hepatectomy.

Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost. Leukotrienes (LT) are a family of eicosanoids with the capacity of signaling to promote proliferation. We analyzed the impact of blocking LT synthesis during liver regeneration after partial hepatectomy (PH). Male Wistar rats were subjected to two-third PH and treated with zileuton, a specific inhibitor of 5-lipoxygenase (5-LOX). Our first find was a significant increment of intrahepatic LTB4 during the first hour after PH together with an increase in 5-LOX expression. Zileuton reduced hepatic LTB4 levels at the moment of hepatectomy and also inhibited the increase in hepatic LTB4. This inhibition produced a delay in liver proliferation as seen by decreased PCNA and cyclin D1 nuclear expression 24 h post-PH. Results also showed that hepatic LTB4 diminution by zileuton was associated with a decrease in NF-ĸB activity. Additionally, decreased hepatic LTB4 levels by zileuton affected the recruitment of neutrophils and macrophages. Non-parenchymal cells (NPCs) from zileuton-treated PH-rats displayed higher apoptosis than NPCs from PH control rats. In conclusion, the present work provides evidences that 5-LOX activation and its product LTB4 are involved in the initial signaling events for liver regeneration after PH and the pharmacological inhibition of this enzyme can delay the initial time course of the phenomenon.

First approaches for the transplantation of hepatocytes from Wistar rat preneoplastic livers into healthy recipients

Background: the shortage of donors of hepatocyte transplantation therapy led to the use of so-called marginal donors. Some donors may have a hepatic illnesses that is associated with hepatic preneoplasia with foci of altered hepatocytes (FAH). Aims: to determine whether recipients developed FAH upon transplantation with hepatocytes from a preneoplastic liver and whether FAH progresses to a preneoplastic hepatocyte-derived tumor (PHDT), up to 60 days after transplantation. Material and methods: male Wistar adult rats were used as donors and recipients. Donors underwent a 2-phase model of liver preneoplasia for hepatocyte isolation. Recipients underwent a partial two thirds hepatectomy and received 150,000 hepatocytes. Recipients were euthanized seven and 60 days after transplantation. The number of FAH per liver area, percentage of liver occupied by FAH, the hepatic enzymatic profile, the percentage of prothrombin time (PT), the proliferative index (PI) and liver morphology were analyzed. Results: recipients developed few and very isolated FAH. No statistical differences were found between hepatic enzyme activities and PT. There were no differences between the groups with regard to the number of FAH per liver area and percentage of liver occupied by FAH after 60 days. The PI decreased on day 60 compared to day seven. No morphological alterations were found. Conclusions: recipients developed few FAH that did not increase in number or size, nor did they progress to PHDT and had normal plasma biochemical features and liver morphology up to 60 days post-transplant. Additional studies are needed to determine whether FAH development constitutes a risk for recipients while waiting for whole organ transplant

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