The Role of Nonparenchymal Cells and Inflammatory Macrophages in Hepatotoxicity
Nonparenchymal cells, in particular macrophages, endothelial cells, and stellate cells, have been implicated in the pathogenesis of hepatotoxicity induced by a number of different xenobiotics. Following exposure of experimental animals to hepatotoxicants, these cells, together with newly recruited inflammatory macrophages, are "activated" to release a wide array of proinflammatory and cytotoxic mediators that have the capacity to promote liver damage. These findings, together with the discovery that hepatotoxicity can be modified by agents that modulate inflammatory cell and nonparenchymal cell functioning, provide direct evidence that these cells contribute to tissue injury. The cytotoxic process most likely involves mediatms such as reactive
active oxygen intermediates, reactive nitrogen intermediates, cytokines, hydrolytic enzymes, eicosanoids, and lipid mediators released at the site of tissue injury. Whereas some of the mediators are directly cytotoxic (i.e., hydrogen peroxide, nitric oxide, peroxynitrite), others degrade the extracellular matrix (i.e., collagenase, elastase) or promote inflammatory cell infiltration and adhesion and nonparenchymal cell proliferation and activation (i.e., chemokines, colony-stimulating factors, interleukin-1 [IL-l], interleukin-6 [IL-6), tumor necrosis factor-a [TNF-a], and platelet-activating factor). There is also evidence that activated nonparenchymal cells produce mediators that can modify hepatocyte protein and nucleic acid biosynthesis as well as cytochrome P450-mediated xenobiotic metabolism. This may also contribute to hepatotoxicity. This chapter reviews experimental data implicating nonparenchymal cells and inflammatory macrophages in hepatotoxicity.