RESPIRATORY CARCINOGENESIS BY CHEMICAL AND PHYSICAL FACTORS

利用肺组织研究了分子标记和基因改变。 F344大鼠经二氧化硅(12 mg Min-U-Sil 5石英)处理后， 气管内滴注。这是一种独特的研究动物模型。 纤维化相关性周围型肺癌的发病机制。它 周围型肺癌的发病率很高，源于过度的肺癌 可塑的肺泡II型上皮细胞，与矽肺颗粒相邻。 玛斯。完成了转化生长因子-β1分布的研究(对于观察到的大鼠 6个月或更长时间)，在矽肺肉芽肿和邻近的肺泡中 II型增生性病变、腺瘤和癌，免疫组织化学染色。 针对合成肽的多克隆抗体，对应于成熟的 和前体转化生长因子-β1定位如下：转化生长因子-β1前体 在矽肺肉芽肿附近的增生型II型细胞中， 腺瘤样增生和腺瘤，但不在癌中；成熟的 转化生长因子-β1定位于成纤维细胞和巨噬细胞内。 与II型增生性病变相邻的矽肺肉芽肿周边 细胞，以及细胞外邻近的结缔组织基质中 增生型II型细胞。这些发现表明了致病作用 对于肺泡II型细胞产生的转化生长因子-β1，两者在矽肺 以及相关的致癌作用。增加泛反应性RAS的数量 P21蛋白定位于增生性肺泡II型细胞，但不表达 在腺瘤和癌中。P53的免疫组织化学定位 用多克隆抗血清(CM-1)检测到的蛋白具有核反应性。 25%的癌，而在正常、增生性或腺瘤中无一例 II型细胞。建立了一种提取分子RNA的方法。 石蜡包埋大鼠肺组织中二氧化硅的分析 癌症。从提取的RNA中提取的DNA进行聚合酶链式反应， 还有从显微解剖的癌组织中提取的DNA， 随后进行单链构象多态(SSCP)分析和 直接DNA测序，到目前为止还没有显示出外显子1的点突变 Ras基因和大鼠P53基因的外显子4-8。

Molecular markers and gene alterations were studied, using lung tissues from F344 rats treated with silica (12 mg Min-U-Sil 5 quartz), by single intratracheal instillation. This is a unique animal model for studying the pathogenesis of fibrosis-associated peripheral lung carcinomas. It yields a high incidence of peripheral lung carcinomas, derived from hyper- plastic alveolar type II epithelial cells, adjacent to silicotic granulo- mas. A study of TGF-beta1 distribution was completed (for rats observed for 6 months or longer), in silicotic granulomas and in adjacent alveolar type II hyperplasias, adenomas and carcinomas, using immunohistochemistry. Polyclonal antibodies to synthetic peptides, corresponding to the mature and precursor TGF-beta1, were localized as follows: TGF-beta1 precursor in the hyperplastic type II cells adjacent to silicotic granulomas, adenomatoid proliferations and adenomas, but not in carcinomas; mature TGF-beta1 was localized intracellularly in fibroblasts and macrophages at the periphery of silicotic granulomas adjacent to hyperplastic type II cells, and extracellularly in the connective tissue matrix adjacent to hyperplastic type II cells. These findings suggest a pathogenetic role for TGF-beta1 produced in the alveolar type II cells, both in silicosis and in associated carcinogenesis. Increased amounts of pan-reactive ras p21 protein were localized in hyperplastic alveolar type II cells, but not in adenomas and carcinomas. Immunohistochemical localization of p53 protein, using polyclonal antisera (CM-1) revealed nuclear reactivity in 25% of the carcinomas, but none in normal, hyperplastic or adenomatous type II cells. An RNA extraction method was developed for molecular analyses using paraffin embedded rat lung tissues with silica-associated carcinomas. Polymerase chain reaction on cDNA derived from extracted RNA, and also on extracted DNA, obtained from microdissected carcinomas, followed by single strand conformational polymorphism (SSCP) analysis and direct DNA sequencing, have so far showed no point mutations in exon 1 of the ras gene and exons 4-8 of the rat p53 gene.