RESPIRATORY CARCINOGENESIS BY CHEMICAL AND PHYSICAL FACTORS

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Histological studies of human lungs from subjects with pneumoconioses and/or lung cancer revealed several cases of alveolar type II hyperplasia adjacent to fibrotic lesions and in proximity to deposits of birefringent dust particles. This novel observation suggests an analogy with the preneoplastic epithelial reactions in the rat model of silicosis- associated lung carcinogenesis. Immunohistochemical localization of TGF- beta1 precursor, after intratracheal instillation of quartz, showed significant differences between rats (susceptible to silica-induced lung carcinogenesis) and two resistant species, mice and hamsters. In rats, TGF-beta1 precursor was detected as early as 10 days and it progressed to a marked level of expression in hyperplastic alveolar type II cells. TGF-beta1 production was minimal in mice and not detectable in hamsters. Immunohistochemical localization of pan-reactive p21 ras protein was further demonstrated in hyperplastic alveolar type II cells of silica- treated rat lungs, but not in adenomas and carcinomas. Thus, both TGF- beta1 precursor and ras p21 protein are expressed in hyperplastic alveolar type II cells and both downregulated in carcinomas, whereas in adenomas only p21 ras protein appears downregulated in the presence of TGF-beta1 precursor; these are proposed as diagnostic markers. Silica particles were demonstrated in alveolar type II cells by electron microscopy (EM), following intrabronchial instillation in rats. The role of crystalline silica in fibrogenesis and its effects on epithelial cells were studied in the liver after subcutaneous injection of quartz in nude mice. Diffuse hepatic silicotic granulomas were associated with bridging necrosis, intrasinusoidal and portal fibrosis and regenerative nodules at 3 and 6 months. By 1 year, large confluent granulomas and severe fibrosis (cirrhosis) disrupted the liver architecture. Silica particles were demonstrated by EM in hypertrophied Kupffer cells and fat-storing Ito cells. Mice are observed for possible development of liver carcinomas. This is the first evidence that silica is fibrogenic and cirrhogenic in the nude mouse liver. This model is used for cytokine and gene expression studies in silica-induced mesenchymal-epithelial interactions.