Abstract
Gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. The effect of GD was studied in reference to postnecrotic liver regeneration induced in rats by thioacetamide (TA). Rats, intravenously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Hepatocytes were isolated from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication, and samples of blood and liver were obtained. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the time course of DNA distribution and ploidy were assayed in isolated hepatocytes. The levels of circulating cytokine TNFα was assayed in serum samples. TNFα was also determined by RT-PCR in liver extracts. The results showed that GD significantly reduced the extent of necrosis. The effect of GD induced noticeable changes in the post-necrotic regeneration, causing an increased percentage of hepatocytes in S phase of the cell cycle. Hepatocytes increased their proliferation as a result of these changes. TNFα expression and serum level were diminished in rats pretreated with GD. Thus, GD pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. No evidence of TNFα implication in this enhancement of hepatocyte proliferation and liver regeneration was found. These results demonstrate that Kupffer cells are involved in TA-induced liver damage, as well as and also in the postnecrotic proliferative liver states.
Highlights
IntroductionGadolinium chloride (GD) is a selective Kupffer cell toxicant that completely eliminates large
Gadolinium chloride (GD) is a selective Kupffer cell toxicant that completely eliminates largeKupffer cells from the liver and has been extensively used in mechanistic studies of hepatotoxic processes [1]
As it is generally accepted that the Kupffer cell function is involved in the severity of liver damage induced by drugs, and that GD induces a selective blockade of Kupffer cell function when administered intravenously, the purpose of the present study is to elucidate the role of Kupffer cells in regeneration after liver injury, blocking Kupffer cell function by GD
Summary
Gadolinium chloride (GD) is a selective Kupffer cell toxicant that completely eliminates large. Kupffer cells from the liver and has been extensively used in mechanistic studies of hepatotoxic processes [1]. As the macrophages residing in the sinusoids of the liver, are the first macrophage population to come into contact with drugs. These cells are anchored to the endothelium in the lumen of the sinusoids [2]. GD, most likely, is protective because it prevents the release of inflammatory cytokines and toxic oxygen radicals produced by activated Kupffer cells [5,6]
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