ABSTRACT
I. INTRODUCTION Over the past several years considerable evidence has accumulated demonstrating that hepatotoxicity induced by a diverse group of drugs and chemicals is due not only to a direct effect of these compounds on the liver, but also indirectly to the actions of inflammatory mediators released by nonparenchymal cells, in particular macrophages, endothelial cells, and stellate cells, as well as infiltrating leukocytes. Following exposure of experimental animals to hepatotoxicants, these cells become “activated.” This involves alterations in their functional and biochemical properties leading to the release of an array of proinflammatory and cytotoxic mediators that have the capacity to promote liver damage. These findings, together with the observation that hepatotoxicity can be modified by agents that modulate inflammatory cell and mediator activity, provide direct evidence that these cells contribute to tissue injury. The mediators involved in the cytotoxic process include reactive oxygen and reactive nitrogen intermediates, proinflammatory cytokines,
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proteolytic enzymes, eicosanoids, and/or bioactive lipids released at sites of injury. Whereas some of these mediators are directly cytotoxic (e.g., hydrogen peroxide, nitric oxide, peroxynitrite), others degrade the extracellular matrix (e.g., collagenase, elastase) and/or promote inflammatory cell adhesion and infiltration, and nonparenchymal cell proliferation and activation [e.g., interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNFα), transforming growth factor-β, (TGFβ), platelet-activating factor (PAF), chemokines, and colony-stimulating factors]. There is also evidence that some of the mediators produced by activated nonparenchymal cells and inflammatory macrophages can modify hepatocyte protein and nucleic acid biosynthesis, as well as cytochrome P450mediated xenobiotic metabolism, which may also contribute to hepatotoxicity. In this chapter experimental evidence implicating nonparenchymal cells and inflammatory macrophages and mediators produced by these cells in hepatotoxicity is reviewed.
