Williams A O, Knapton A D
Laboratory of Experimental Pathology, Division of Cancer Etiology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hepatology. 1996 May;23(5):1268-75. doi: 10.1002/hep.510230548.
Hepatic silicosis, cirrhosis, liver cell adenoma, and carcinomas developed in nude mice (NCr-Nu) given quartz by the subcutaneous and intraperitoneal routes. Syrian golden hamsters (15:16 EHS:cr) given quartz by both routes developed extensive fibrosis and cirrhosis and had higher morbidity and mortality rates after 3 months. Crystalline silica (quartz) induces fibrosis, adenomas, and carcinomas in the lungs of Fisher 344 rats, but certain strains of mice and hamsters are resistant to quartz-induced pulmonary carcinogenesis. Pulmonary fibrosis, however, is minimal in mice and absent in hamsters who received quartz intratracheally. To determine whether species differences are due to organ-specific rather than species-specific factors, susceptibility of the liver to quartz toxicity was investigated in nude mice and hamsters. The present study shows that the differential manifestations of quartz toxicity by these rodent species are dependent on factors that are organ-specific rather than host-specific. At 3 months, hepatocytes in mice were immunostained with intracellular transforming growth factor (TGF) beta 1 (LC 1-30) but not with TGF-beta 1 latency-associated peptide (LAP) protein (266-278); at 12 months, hepatocytes were immunostained with TGF-beta 1 LAP (266-278) but not with TGF-beta 1 (LC1-30). The hepatocytes of hamsters at 3 months showed immunoreactivities to TGF-beta 1 LAP (266-278) and TGF-beta 1 (LC1-30); immunostaining to TGF-beta 1 (LC1-30) was detected in nonparenchymal cells. Extracellular TGF-beta 1 (CC1-30) was detected in the silicotic granulomas and fibrous tissue in livers of both species. Quartz-induced liver carcinoma did not express TGF-beta 1 LAP (266-278) and LC (1-30) proteins, but these were detected in the cells of the adenoma in the same liver. Control animals showed no hepatic lesions nor immunoreactivity to TGF-beta 1. The spatial and temporal patterns of expression of TGF-beta 1, TGF-beta 2, TGF-beta receptor type II messenger RNAs (mRNAs), and TGF-beta 1 proteins in the different hepatic lesions suggests that TGF-beta isoforms may play a role in the pathogenesis of quartz-induced fibrosis, cirrhosis, liver cell adenoma, and carcinoma.
通过皮下和腹腔内途径给裸鼠（NCr-Nu）注射石英后，其出现了肝硅沉着病、肝硬化、肝细胞腺瘤和癌。通过这两种途径给叙利亚金黄地鼠（15:16 EHS:cr）注射石英后，其出现了广泛的纤维化和肝硬化，且3个月后的发病率和死亡率更高。结晶二氧化硅（石英）可在Fischer 344大鼠的肺部诱发纤维化、腺瘤和癌，但某些品系的小鼠和地鼠对石英诱发的肺癌具有抗性。然而，经气管内注射石英的小鼠肺部纤维化程度较轻，地鼠则无纤维化。为了确定物种差异是由于器官特异性因素而非物种特异性因素导致的，研究了裸鼠和地鼠肝脏对石英毒性的易感性。本研究表明，这些啮齿动物物种对石英毒性的不同表现取决于器官特异性因素而非宿主特异性因素。3个月时，小鼠肝细胞经细胞内转化生长因子（TGF）β1（LC 1-30）免疫染色，但未被TGF-β1潜伏相关肽（LAP）蛋白（266-278）免疫染色；12个月时，肝细胞经TGF-β1 LAP（266-278）免疫染色，但未被TGF-β1（LC1-30）免疫染色。3个月时地鼠的肝细胞对TGF-β1 LAP（266-278）和TGF-β1（LC1-30）均有免疫反应性；在非实质细胞中检测到了对TGF-β1（LC1-30）的免疫染色。在两种物种肝脏的硅沉着性肉芽肿和纤维组织中均检测到了细胞外TGF-β1（CC1-30）。石英诱发的肝癌未表达TGF-β1 LAP（266-278）和LC（1-30）蛋白，但在同一肝脏腺瘤的细胞中检测到了这些蛋白。对照动物未出现肝脏病变，对TGF-β1也无免疫反应性。不同肝脏病变中TGF-β1、TGF-β2、II型TGF-β受体信使核糖核酸（mRNA）和TGF-β1蛋白的时空表达模式表明，TGF-β亚型可能在石英诱发的纤维化、肝硬化、肝细胞腺瘤和癌的发病机制中起作用。
