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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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Received May 22, 2003; accepted June 18, 2003
© 2003 Society of Toxicology

Immunotoxicology

Silica Induced Caspase Activation in Mouse Alveolar Macrophages Is Dependent upon Mitochondrial Integrity and Aspartic Proteolysis

Michael Thibodeau 1, Charles Giardina 2, and Andrea K. Hubbard 1*

1 Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269
2 Department of Molecular & Cell Biology, University of Connecticut, Storrs, CT, 06269

* To whom correspondence should be addressed. E-mail: Andrea.Hubbard{at}uconn.edu.


  Abstract

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 {alpha}-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.

Key Words: Silica, Apoptosis, Caspase 3, Caspase 9, Mitochondria, Cathepsins .


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