ToxSci Advance Access published online on July 11, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg178
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269
* To whom correspondence should be addressed. E-mail: Andrea.Hubbard{at}uconn.edu.
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
© 2003 Society of Toxicology
Immunotoxicology
Silica Induced Caspase Activation in Mouse Alveolar Macrophages Is Dependent upon Mitochondrial Integrity and Aspartic Proteolysis
2 Department of Molecular & Cell Biology, University of Connecticut, Storrs, CT, 06269
Abstract 
-quartz silica exposure (12.5 ug/cm2 to 50 ug/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 hrs as measured by the appearance of subdiploid cell fragments in a flow cytometric analysis. Exposure to TiO2 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 hrs 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.
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