Exposure to silica dust can result in lung inflammation that may progress to 
fibrosis, for which there is no effective clinical treatment. The mechanisms 
involved in the development of pulmonary silicosis have not been well defined; 
however, most current evidence implicates a central role for alveolar 
macrophages (AM) in this process. We propose that the fibrotic potential of a 
particulate depends upon its ability to cause apoptosis in AM. In this study, 
human AM were treated with fibrogenic, poorly fibrogenic, and nonfibrogenic 
model particulates, such as silica (133 micrograms/ml), amorphous silica (80 
micrograms/ml), and titanium dioxide (60 micrograms/ml), respectively. Cell were 
treated with these particulates in vitro for 6 and 24 hr and examined for 
apoptosis by morphological analysis, DNA fragmentation, and levels of cytosolic 
histone-bound DNA fragments (cell death ELISA assays). Treatment with silica 
resulted in morphological changes typical of apoptotic cells, enhanced DNA 
fragmentation (a characteristic feature of programmed cell death), and 
significant alveolar macrophage apoptosis as observed by cell death ELISA 
assays. In contrast, amorphous silica and titanium dioxide demonstrated no 
significant apoptotic potential. To elucidate the possible mechanism by which 
silica causes apoptosis, we investigated the role of the scavenger receptor (SR) 
in silica-induced apoptosis. Cells were pretreated with and without SR ligand 
binding inhibitor, polyinosinic acid (poly(I), 500 micrograms/ml), for 10 min 
prior to silica treatment. Pretreatment with poly(I) resulted in complete 
inhibition of silica-induced apoptosis as measured by cell death ELISA. Further, 
we examined the involvement of interleukin-converting enzyme (ICE) in 
silica-mediated apoptosis using an ICE inhibitor, Z-Val-Ala-Asp-fluoromethyl 
ketone. Z-Val-Ala-Asp-fluoromethyl ketone inhibited silica-induced apoptosis and 
IL-1 beta release. These results suggest that fibrogenic particulates, such as 
silica, caused apoptosis of alveolar macrophages and that this apoptotic 
potential of fibrogenic particulates may be a critical factor in initiating an 
inflammatory response resulting in fibrosis. Additionally, silica-induced 
apoptosis of alveolar macrophages may be due to the interaction of silica 
particulates with the SR, initiating one or a number of signaling pathways 
involving ICE, ultimately leading to apoptosis.