ToxSci Advance Access originally published online on July 11, 2003
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Toxicological Sciences 76, 91-101 (2003)
Copyright © 2003 by the Society of Toxicology
IMMUNOTOXICOLOGY |
Silica-Induced Caspase Activation in Mouse Alveolar Macrophages Is Dependent upon Mitochondrial Integrity and Aspartic Proteolysis
* Departments of Pharmaceutical Sciences and
Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269
Although silica has been documented to cause apoptotic cell death, the cellular pathways leading to caspase activation have not been extensively investigated. Here we demonstrate in a mouse macrophage cell line (MH-S cells) that 
-quartz silica exposure (12.5 µg/cm2 to 50 µg/cm2) elicited activation of both caspase 3 and caspase 9, whereas anatase titanium dioxide (TiO2), a non-fibrogenic particle, did not. Silica exposure in vitro also induced apoptosis after 6 h, as measured by the appearance of subdiploid cell fragments in a flow cytometric analysis. Exposure to TiO 2 did not elicit significant apoptosis. Silica-induced apoptosis and caspase 3 activation were, in part, caspase 9 dependent, as determined by their sensitivity to either a general caspase inhibitor (Z-VAD-FMK) or a specific caspase 9 inhibitor (Z-LEHD-FMK). Silica exposure in vitro also elicited significant mitochondrial depolarization after 2 and 6 h of exposure. Cyclosporin A, an inhibitor of the mitochondrial permeability pore, partially decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, suggesting a role for mitochondrial dysfunction in these events. Pepstatin A, an inhibitor of cathepsin D, also decreased mitochondrial depolarization, caspase 3 activation, and caspase 9 activation, whereas leupeptin, an inhibitor of cathepsin B, had no effect. These data suggest that short-term silica exposure in vitro induces both caspase 3 and caspase 9 activity, which appears to participate in apoptosis. Activation of these caspases seems to be dependent, in part, on aspartic proteolysis and loss of mitochondrial integrity.
Key Words: silica; apoptosis; caspase 3; caspase 9; mitochondria; cathepsins.
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