Abstract
The association of silica with pulmonary inflammation and fibrosis is well documented. However, the mediators involved in the pathogenesis of silica-induced pulmonary fibrosis are not completely defined. In parallel studies, which will be summarized in this presentation, intratracheal instillation of silica resulted in nitric oxide production and pulmonary inflammation within 24 hours. The objective of the current study was to determine the involvement of nitric oxide and cytokines in the pathogenesis of inflammation and fibrosis associated with an occupationally-relevant inhaled exposure to silica. Male Fischer rats were exposed by inhalation to 2 mg/m3 of freshly-generated silica for 2 weeks, 2 months, and 6 months at a rate of 5 days/week, 8 hour per day. Cellular differentials, chemiluminescence, and mRNA levels of inducible nitric oxide synthase (iNOS), transforming growth factor β (TGFβ), and platelet-derived growth factor (PDGF) were all measured in cells obtained by bronchoalveolar lavage. Tissue histopathology and hydroxyproline content were examined for evidence of pulmonary fibrosis and collagen production, respectively. Cellular differentials showed that red blood cells (RBC) and leukocytes were both increased after 2 and 6 months of exposure, indicating pulmonary damage and inflammation. In addition, both total and NO-dependent chemiluminescence were increased after 2 and 6 months of exposure, suggesting that oxygen radicals and nitric oxide were being produced by the bronchoalveolar lavage cells. Northern analysis revealed that mRNA levels for iNOS was increased after 2 months, but returned to normal levels after 6 months. Pathological examination revealed multiple granulomatous lesions after 6 months characterized by focal, subpleural epithelial proliferation, and early stages of fibrosis. At 6 months, there was a small but significant increase in the hydroxyproline content suggesting collagen synthesis. TGFβ mRNA level were elevated after 6 months, but PDGF mRNA was not different than controls. The results suggest that exposure to 2 mg/m3 of silica results in pulmonary damage and inflammation after 2 months of exposure. After 6 months, there is evidence of early pulmonary fibrosis characterized by granulomatous lesions, increased hydroxyproline content, and increased TGFβ synthesis.