SILICA-INDUCED APOPTOSIS MEDIATED VIA SCAVENGER RECEPTOR IN HUMAN ALVEOLAR MACROPHAGES

Exposure to silica dust can result in lung inflammation that may progr ess to fibrosis, for which there is no effective clinical treatment, T he mechanisms involved in the development of pulmonary silicosis have not been well defined; however, most current evidence implicates a cen tral role for alveolar macrophages (AM) in this process, We propose th at the fibrotic potential of a particulate depends upon its ability to cause apoptosis in AM, In this study, human AIM were treated with fib rogenic, poorly fibrogenic, and nonfibrogenic model particulates, such as silica (133 mu g/ml), amorphous silica (80 mu g/ml), and titanium dioxide (60 mu g/ml), respectively. Cells were treated with these part iculates in vitro for 6 and 24 hr and examined for apoptosis by morpho logical analysis, DNA fragmentation, and levels of cytosolic histone-b ound DNA fragments (cell death ELISA assays), Treatment with silica re sulted in morphological changes typical of apoptotic cells, enhanced D NA fragmentation (a characteristic feature of programmed cell death), and significant alveolar macrophage apoptosis as observed by cell deat h ELISA assays, In contrast, amorphous silica and titanium dioxide dem onstrated no significant apoptotic potential, To elucidate the possibl e mechanism by which silica causes apoptosis, we investigated the role of the scavenger receptor (SR) in silica-induced apoptosis, Cells wer e pretreated with and without SR ligand binding inhibitor, polyinosini c acid (poly(I), 500 mu g/ml), for 10 min prior to silica treatment, P retreatment with poly(I) resulted in complete inhibition of silica-ind uced apoptosis as measured by cell death ELISA. Further, we examined t he involvement of interleukin-converting enzyme (ICE) in silica-mediat ed 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 particul ates, such as silica, caused apoptosis of alveolar macrophages and tha t this apoptotic potential of fibrogenic particulates may be a critica l 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 leadi ng to apoptosis. (C) 1996 Academic Press, Inc.