Early Role of Lipid Inflammatory Mediators in Silica Toxicity: Possible Methods to Detoxify Silica

"I. INTRODUCTION(SILICA, THE LUNG, INFLAMMATION, AND FIBROSIS)Inhalation of respirable-size silica (0. I to 5 µm in diameter) deposits the particles in the deep spaces of the Jung where oxygen is exchanged. The resulting pattern of inflammation is substantially different compared to that observed from other inhaled substances such as carbon, polystyrene titanium dioxide etc. 1 Following the inflammatory reaction the body attempts to isolate the damage by walling off the area via fibrosis. 2 The unique nature of the inflammatory response to silica makes it logical to infer that fibrosis is a later-stage manifestation of the initial inflammatory damage. In addition to the inflammation extensive lysis and cellular death particularly to macrophages and neutrophils, can occur, depending on the dose of silica.' The ingestion of significant amounts of silica by macrophages and neutrophils produces an inflammatory sequence which activates the lipoxygenase pathway of arachidonic acid metabolism and produces platelet activating factor (PAF) and leukotrienes (LT).4·5II. CALCIUM IONOPHORE MIMICS SILICA TOXICITY IN VITROPhagocytic cells exposed to silica in vitro produce PAF and LT. This response is reminiscent of phagocytic cells exposed to the calcium ionophore (A23 l 87) in the presence of ionic calcium.6-8 A23 l 87 forms a complex with free ionic calcium which passes through cellular membranes, thus transporting calcium inside the cell. The increased intracellular calcium concentration triggers the production of small amounts of prostaglandins large amounts of LT. PAF and. depending on dose cellular death (see Figure 1 ). Could silica cause LT production and cellular death by a similar mechanism? How could silica - an inert solid - act in a similar fashion as a soluble stimulant? Clearly the negative SiO2 and OH- surface of silica can bind calcium ions9 and therefore could theoretically act as a solid-state ionophore releasing bound calcium inside of cells following phagocytosis."