Abstract
Transforming growth factor β1 (TGF-β1), ras, and p53 were studied in the rat model for silica-induced fibrogenesis and carcinogenesis, and in the FRLE cell line, derived from fetal rat alveolar pneumocytes. In Fischer-344 rats of both sexes, following single intratracheal instillation of quartz, mesenchymal and epithelial lung reactions were examined immunohistochemically for reactivity to (1) intracellular mature TGF-β1, localized in fibroblasts and macrophages at the periphery of silicotic granulomas adjacent to hyperplastic alveolar type II (HP-TII) cells; (2) extracellular mature TGF-β1, localized in connective tissue matrix adjacent to HP-TII cells; and (3) TGF-β1 precursor/latency-associated peptide (LAP), localized intracellularly in HP-TII cells and in adenomas, but not in carcinomas. Immunoreactivity to the three antibodies for TGF-β1 was first detected between 10 and 15 days from treatment. Hematite-treated controls showed no reactivity to TGF-β1. Production of TGF-β1 by HP-TII cells is suggested to play a pathogenetic role in silica-induced mesenchymal and epithelial lesions. The role of other cytokines requires further investigation. Panreactive p21 ras protein, in silica-treated rat lungs, was strongly immunoreactive in HP-TII cells adjacent to granulomas and forming adenomatoid lesions, but not in adenomas and carcinomas, nor in control rat lungs. Thus, adenomas were positive for TGF-β1 precursor/LAP but negative for p21 ras protein; carcinomas were negative for both. Nuclear immunoreactivity to p53 was found in 25 percent of silica-induced carcinomas. FRLE cells showed no detectable immunoreactivity to TGF-β1 isoforms, but FRLE neoplastic transformants were immunoreactive for TGF-β1 precursor/LAP. The relationships between TGF-β1, p53, and ras genes are investigated as factors in silicosis-associated lung carcinogenesis. Histological examination of human lungs with silicosis or coalworkers' pneumoconiosis revealed foci of proliferating alveolar epithelial cells adjacent to areas of fibrosis, analogous to the rat model; the epithelial cells were immunoreactive to TGF-β1 precursor/LAP. Further investigation of pulmonary pathology in human silicotics, with or without lung cancer, may provide a basis for the interpretation of pathogenetic mechanisms in silicosis-associated lung cancer. Williams, A.O.; Knapton, A.D.; Saffiotti, U.: Growth Factors and Gene Expression in Silica-Induced Fibrogenesis and Carcinogenesis. Appl. Occup. Environ. Hyg. 10(12):1089–1098;1995.