Silica-Induced Inflammatory Mediators and Pulmonary Fibrosis

Silicosis continues to be a lung disease with significant morbidity and mortality. Although silicainduced lung injury and cell activation and/or death has been investigated over the past several years, basic research continues to reveal the cell: cell and cell: mediator interactions critical to these events. This Chapter will emphasize the production and participation of several inflammatory cytokines, mediators and cell processes in the development of silica-induced lung injury and fibrosis. Mediators to be discussed will include TNFα, IFNγ, IL-1β, IL-12, IL-18, IL-9, TGFβ, MMPs/TIMPs, ROS/RNS, caspases and Fas/FasL in the processes of cell activation, cell proliferation and cell death. The mediator networks and apoptotic pathways elicited by this inorganic particle are complex, driven by many cell types and affect numerous cell functions. Understanding these interactions will help in developing strategies for therapeutic intervention at different stages of the disease. Silica and Silicosis In the United States alone, silicosis was listed as a primary or contributing cause of death in 4313 individuals from 1979-1990. With the significant occupational health risk posed by silica exposure, research endeavors to explore the cellular and inflammatory mechanisms underlying silica induced lung injury are critical. Silica-Induced Lung Injury (Fig 1) Much of the research that describes human silicosis is the result of investigations in animal models of silica-induced lung injury. In instances of low levels of silica exposure, there can be sufficient clearance to result in minimal toxicity and resolution of cell injury. At higher levels of exposure, there is crystal deposition at the alveolar duct bifurcations, phagocytosis of particles and a rapid influx of neutrophils (PMNs) and monocytes into the alveoli. Phagocytosis by alveolar inflammatory cells may result in cell activation or cell death due to apoptosis or necrosis-the latter resulting in the release of lysosomal enzymes and lactate dehydrogenase (LDH). In addition, there is the generation of inflammatory cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS) by pulmonary macrophages, lymphocytes and bronchiolar and alveolar epithelial cells eliciting focal damage to type I epithelial cells. In response to this damage, silica exposure is documented to cause proliferation of type © 20 04 C op yr ig ht Eu re ka h / L an de s Bi os ci en ce D o N ot D is tri bu te Fibrogenesis: Cellular and Molecular Basis 202 II epithelial cells at low doses and cell death at higher doses. Silica induced activation of pulmonary cells, and the subsequent release of inflammatory mediators and fibrogenic factors, appears to lead to pulmonary fibrosis. As a reflection of this fibrotic response, animals exposed to silica also evidence impaired lung function (e.g., decreased lung compliance, vital capacity and diffusion capacity). Silica-Induced Mediators in Pulmonary Fibrosis Most pulmonary fibrosis begins in the alveolus and develops in definable stages over time with epithelial cell injury and alveolar inflammation, organization of the ensuing alveolar exudates and incorporation of the alveolar fibroproliferative process into alveolar walls. Repeating cycles of these events can lead to the characteristic signature of distorted and dysfunctional lung parenchyma. Integral in the understanding of the cellular and molecular basis of silica induced pulmonary fibrosis is the examination of silica induced inflammatory mediators in this process. Tumor Necrosis Factor α (TNFα) TNFα primarily produced by activated macrophages is a cytokine with numerous pro-inflammatory effects (e.g., macrophage activation, adhesion molecule expression, lymphoFigure 1. Silica-Induced Cell Injury and Resulting Mediator Release. At levels of low silica exposure, there may be little cell damage and ultimate resolution of injury with return to normal structure. Alternately, at higher levels of exposure, there may be cell death by either apoptotic and/or necrotic pathways with compensatory cell proliferation. With the initiation of a leukocyte inflammatory response, there is resulting activation of multiple cell types including macrophages, lymphocytes, and epithelial cells (bronchiolar, alveolar) with the production of numerous mediators leading to the dysregulation of collagen production by fibroblasts and ensuing fibrosis.