Abstract
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.
Highlights
Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost
In order to establish if liver regeneration was affected by zileuton, we first analyzed liver weight to body weight (LW/BW) ratio after partial hepatectomy (PH)
Our study shows a significant increment of hepatic leukotriene B4 (LTB4) levels during the first hours after PH together with an increase in 5-LOX expression
Summary
Regeneration is the unmatched liver ability for recovering its functional mass after tissue lost. Zileuton reduced hepatic LTB4 levels at the moment of hepatectomy and 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. 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. In hepatocellular carcinoma HepG2 cells, LTB4 acts as an activator of NF-kB, a critical factor for cell survival[16] In liver proliferation, it has been highlighted the association between genes related to lipid metabolism and liver regeneration after PH. Using the specific 5-LOX inhibitor, zileuton, we analyzed the impact of blocking the LT producing pathway during liver proliferation after PH
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