Induction of apoptosis by chronically inhaled silica.
Mercer-RR; Millecchia-L; Wang-L; Scabilloni-JF; Castranova-V
Toxicologist 2001 Mar; 60(1):81
Whether apoptosis is induced and/or plays a significant role in lung pathology from inhaled silica is unknown. We examined apoptosis in rat lungs following exposure to 15 mg/m3 silica (average particle size 1.6 um) or filtered air for 6 hours/day, 5 days/week for up to 116 days. Lungs from filtered air and exposed animals were preserved by intra-tracheal instillation of fixative. Additional groups were sacrificed for isolation of genomic DNA. Sections were processed for TdT labeling of apoptotic nuclei and counter-stained with propidium iodide to label non-apoptotic nuclei. Morphometric methods were used to determine the number of apoptotic cells per lung. Additional sections were stained with Sirius Red to detect areas of lung fibrosis. Ladder patterns demonstrating DNA breakdown products of apoptotic nuclei were present in agarose gels of genomic DNA in 79 and 116 day exposure groups. Significant increases in the number of apoptotic nuclei were observed at 40, 79 and 116 days of exposure. At 40 days of exposure, apoptotic nuclei were observed in focal accumulations of lung surfactant and alveolar macrophages. At 79 and 116 days of exposure these masses of lung surfactant and inflammatory cells were more diffusely distributed throughout the airspaces. Fibrosis of the alveolar walls and isolated fibrotic nodules, similar to those in human silicosis, were present at 79 and 116 days of exposure. Apoptotic cells were limited to the airspaces and were not found within areas of fibrosis. These results demonstrate that silical inhalation produces significant increases in apoptosis before and during the development of fibrotic lesions. It is proposed that apoptosis of alveolar macrophages rather than interstitial cells is associated with the development of fibrotic foci in the lungs.
Silica-dusts; Lung; Exposure-levels; Animal-studies; Laboratory-animals; Lung-fibrosis; Silicosis
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California