Silicosis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Silica (silicon dioxide) is the most abundant mineral on earth. Silica exists in crystalline and amorphous forms. Crystalline silica (quartz, cristobalite, and tridymite) is associated with a spectrum of pulmonary diseases. Amorphous forms, including vitreous silica and diatomite (formed from skeletons of prehistoric marine organisms), are relatively less toxic after inhalation [18].
Quartz is the most abundant form of crystalline silica and is a major component of rocks including granite, slate, and sandstone. Granite contains about 30 percent free silica, slate about 40 percent, and sandstone is almost pure silica [19]. Cristobalite and tridymite occur naturally in lava and are formed when quartz or amorphous silica is subjected to very high temperatures.
The toxicity of crystalline silica appears to result from the ability of crystalline silica surfaces to interact with aqueous media, to generate oxygen radicals, and to injure target pulmonary cells such as alveolar macrophages. Resultant generation of inflammatory cytokines (eg, interleukin-1 and tumor necrosis factor beta) by target cells lead to cytokine networking between inflammatory cells and resident pulmonary cells, resulting in inflammation and fibrosis [20].
Lower intensity exposures to silica (78) evoke reversible inflammatory changes characterized by focal aggregations of mineral-laden alveolar macrophages, where as, higher exposures elicit intense and protracted inflammatory changes, cell proliferation in various compartments of the lung, and excessive deposition of collagen and other extracellular matrix components by mesenchymal cells. The AM is implicated as a major cell type in fibrogenesis (reviewed in references 79 and 80). In addition, various cell types of the immune system, including neutrophils (78, 81), T-lymphocytes (29, 82), and mast cells (83, 84) are also implicated in the development of fibrosis. A multiplicity of interactions between these effector cells and “target” cell types of injury, including bronchiolar, alveolar epithelial cells and fibroblasts, may govern the pathogenesis and progression of disease.
Injury to the alveolar type I epithelial cell is regarded as an early event in fibrogenesis followed by hyperplasia and hypertrophy (85) of type II epithelial cells. Silica-induced cell hyperproliferation of mesenchymal cells is also a hallmark of the fibrotic lesion. Proliferation may occur intially at sites of accumulation of inhaled minerals, but later at distal sites where particles or fibers are translocated over time. Alternatively, mitogenic cytokines may mediate signaling events, leading to cell replication at sites physically remote from fibers (89, 90). The initiation of proliferation in epithelial cells and fibroblasts by silica may occur after upregulation of the early response protooncogenes, c-fos, c-jun, and c-myc (77, 91– 93). c-fos and c-jun encode proteins of the Fos and Jun family Increased expression of early response genes and protein products is also linked to the development of apoptosis (97, 98)