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Role of Tumor Necrosis Factor-α in Cadmium-Induced Hepatotoxicity

https://doi.org/10.1006/taap.1995.1065Get rights and content

Abstract

Liver and kidney injury following acute or chronic exposure to cadmium is well characterized. While hepatocytes and endothelial cells of the sinusoids are thought to be the primary cellular targets in the liver, ultrastructural changes may vary depending upon the exposure regimen and the time following administration. Since acute and chronic liver disease is often associated with the presence of cytokines, we investigated the role of proinflammatory cytokines in cadmium-induced hepatotoxicity. Supernatants from cultured liver slices obtained from acute or subchronic cadmium-exposed rats and mice were collected and cytokine secretion was examined. In addition, mRNA transcripts for IL-1α, IL-1β, IL-6, TNF-α, MIP-2, IFN-γ, and ICAM-1 from livers of treated mice were quantitated by reverse transcription-polymerase chain reaction. Modest increases in secretion of TNF-α, IL-1α, and IL-6 were observed in response to cadmium which were enhanced in LPS-primed mice. Additionally, cadmium exposure increased IL-1α, IL-1β, TNF-α, MIP-2, IL-6, and ICAM-1 mRNA transcripts in the liver. Immunohistochemical analysis revealed that TNF-α was associated with nonparenchymal cells in livers of cadmium-treated mice. Cadmium exposure produced a marked increase in plasma hepatocellular enzyme levels (i.e., AST, LDH, SDH), acute phase proteins (i.e., serum amyloid A), and foci formation in the liver, while focal inflammation and serum amyloid A (SAA) secretion, but not plasma enzymes, were further increased in cadmium-exposed mice primed with LPS. SAA secretion and focal inflammation were prevented by pretreatment with antibodies to TNF-α, indicating that these pathological manifestations are cytokine dependent. These data indicate that TNF-α, released from nonparenchymal cells as well as associated cytokines, are responsible for certain manifestations observed with cadmium-induced hepatotoxicity.

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    However, we here found that hepatic injuries were more severe in Hri−/− mice, particularly with the observation of atrophy of central vein. While liver is the most affected organ upon Cd exposure, kidney is considered to be the following damaged organ (Kayama et al., 1995b). In our study, Cd administration was also shown to induce renal injury, similar to previous reports (Dudley et al., 1985; Pari et al., 2007; Satarug et al., 2011).

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