Silica Exposure Induces Cytotoxicity and Proliferative Activity of Type II Pneumocytes

Abstract

The contribution of the type II pneumocyte to the pathogenesis of silicosis is largely unknown. Prominent features of silicosis are hyperplasia and hypertrophy of type II epithelial cells, often accompanied by phospholipid accumulation in the lung. The biologic regulation of these events is poorly understood. This study addresses the question of a direct effect of silica on type II pneumocytes, since direct contact of the inhaled silica dust can occur in vivo. Type II cells were isolated from fetal rat lungs and their epithelial specificity was verified. Experiments were performed on 2nd passage monolayers in 2% serum. Repair, replication, and growth activity was evaluated by the incorporation of[³H]thymidine. Cytotoxicity was measured by quantitating the release of[¹⁴C]adenine and expressed as a cytotoxicity index (CI). Type II cell proliferation and cytotoxicity were evaluated for the mineral dusts silica (SiO₂) aluminum-treated silica (SiO₂AlK), and titanium (TiO₂). Of these mineral dusts, only low concentrations of silica increased type II cell [³H]thymidine incorporation (silica 2.5 μg/mL: 52% above control, P < .05; silica 20 μg/mL: 57% above control, P < .02). In addition, silica increased the cell number significantly, although to a lesser degree. Exposure of the type II epithelial cells to silica dust for 24 h resulted in dose-dependent cytotoxicity (silica 10 μg/mL, CI = 9.1%, P < .0002; 250 μg/mL, CI = 45.1%, P < .0001). SiO₁Al completely suppressed these proliferation and cytotoxicity effects, which were then similar to those of the inert dust, TiO₂. These data suggest that direct exposure and contact of the type II pneumocytes to low-dose silica dust initiated repair, replication, and growth activity, while exposure to higher silica concentrations resulted in marked cytotoxicity. Both the repair, replication, and growth and the cytotoxic responses of the type II epithelial cells to silica exposure are related to the surface properties of silica.