Xenobiotic‐Induced Inflammation: Pathogenesis and Mediators

Abstract

Inflammation is an extremely complex and fascinating adaptive process by which fluid, electrolytes, plasma proteins and leukocytes accumulate in the extravascular spaces, in response to a variety of noxious stimuli. These inducers of inflammation include trauma, infectious agents, neoplastic cells and xenobiotics. Such stimuli are sensed by various cellular mechanisms via complex pathways of intracellular signalling resulting in the release of inflammatory mediators. These mediators comprise a large number of molecules ranging from nitric oxide to small amines, peptides, proteins, lysosomal enzymes and lipid derivatives, which act on target effector cells such as leukocytes, endothelial cells and fibroblasts to change their phenotype and orchestrate the inflammatory process. The function of inflammation is to dilute, contain and remove the inducing stimuli in preparation for healing and regeneration. However, inflammation can persist, resulting in tissue damage and possibly functional compromise. Xenobiotics can induce inflammation by a variety of different mechanisms, many of which result in cell injury, degeneration and/or necrosis, either directly or indirectly, by parent or metabolite. This cytotoxicity may be related to pharmacology or to the generation of toxic intermediates in the affected cells. Xenobiotics may also activate inflammatory/immune cells to release inflammatory mediators in nonspecific ways, or by stimulating a specific immune response. The pattern of morphologic and functional changes induced by these mechanisms differs according to the target cell population affected and persistence of inducing stimuli. The pathogenesis of inflammation at the tissue, cellular and molecular levels is reviewed: these mechanisms also apply to inflammation induced by xenobiotics. It is important to note that superantigen-mediated cytokine release, or immune-mediated mechanisms of inflammation may be poorly predicted by preclinical toxicity studies. A detailed knowledge of the pathogenesis and molecular mechanisms involved in inflammation can facilitate the design of in vitro or in vivo studies to predict or investigate these responses when associated with xenobiotic administration. Keywords: inflammation; pathogenesis; xenobiotic; eicosanoids; cytokines; chemokines; toxicology; hypersensitivity