"""Piggy Back"" Mechanism with Calcium Explains How SilicaExerts Its Toxicity to Phagocytic Cells"

"Using propidium assay and flow cytometry, we examined how silica exerts its toxicity toward phagocytic cells employing the human neutrophil as a model. This toxicity appears to be associated with calcium bound to silica. Once the silica with calcium is phagocytized, the extra calcium causes the death of the cell. Using ""Ca we found that 6 to 10% of millimolar calcium is bound to milligram amounts of respirable-sized silica (diameter of 5 µ.m or less) at physiological pH. If the silica particles arc coated with an organosilanc (Prosil 28). calcium binding is decreased by 60% as is cell death. Pretreating with INDO IAM (a chelator of intracellular calcium) reduces the cellular death by 80%. Nonfibrogcnic particles- polystyrene beads or coal dust-produced 10% or less cell death in a 4-h period. Silica with no added, external calcium appears to exert toxicity to neutrophils; however, pretreating cells with EDT A decreases cellular death to the level of nonfibrogcnic particles. Chronic toxicity with silica-calcium appears similar to the chronic toxicity in gout where particles cause a cycle of inflammation. c 1993 Academic Press, Inc.Silicosis is an occupational disease caused by the inhalation of fine particles of silica, usually between 0.1 and 5 µ.m in diameter (1). A recent hypothesis explaining silica's toxicity suggested that surface free radicals caused damage to cells (2). This explanation appears doubtful, however, since the addition of silica to water, such as that found in biological systems, quenches free radicals; also, such a hypothesis does not provide basis for a persistent inflammatory pattern that lasts for years. Kane et al. (3) proposed that silica's toxicity resulted from an excessive concentration of calcium ions within the phagocytic cell (macrophages). However, the mechanism that was capable of linking silica to an excess of intracellular, ionic calcium was not explained. The surface of silica is certainly involved because covering the surface with polymers or phospholipids decreases silica's toxicity (4-6).When silica is engulfed by macrophages platelet activating factor and leukotrienes are produced (7, 8). This is the same inflammatory pattern produced by phagocytic cells exposed to the calcium ionophore A23187 and ionic calcium. How could silica be acting like A23187? Perhaps calcium binds to silica extracellulary and then is released intracellulary following phagocytosis; the latter process, in a sense a ""piggy back"" process, would permit activation of inflammation and cell death mechanisms."