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Am J Physiol Lung Cell Mol Physiol 280: L10-L17, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 1, L10-L17, January 2001

Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages

Han-Ming Shen1, Zhuo Zhang2, Qi-Feng Zhang2, and Choon-Nam Ong1

1 Department of Community, Occupational, and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore; and 2 Pneumoconiosis Division, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310013, Peoples Republic of China

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.

terminal deoxynucleotidyltransferase-mediated deoxyuridine 5'-triphosphate nick end-labeling assay; poly(adenosine 5'-diphosphate-ribose) polymerase; ebselen; antioxidants


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