HEPATIC SILICOSIS, CIRRHOSIS, AND LIVER-TUMORS IN MICE AND HAMSTERS -STUDIES OF TRANSFORMING GROWTH-FACTOR-BETA EXPRESSION

Hepatic silicosis, cirrhosis, liver cell adenoma, and carcinomas devel oped in nude mice (NCr-Nu) given quartz by the subcutaneous and intrap eritoneal routes, Syrian golden hamsters (15:16 EHS:cr) given quartz b y both routes developed extensive fibrosis and cirrhosis and had highe r morbidity and mortality rates after 3 months. Crystalline silica (qu artz) induces fibrosis, adenomas, and carcinomas in the lungs of Fishe r 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 intratra cheally. To determine whether species differences are due to organ-spe cific rather than species-specific factors, susceptibility of the live r to quartz toxicity was investigated in nude mice and hamsters, The p resent study shows that the differential manifestations of quartz toxi city by these rodent species are dependent on factors that are organ-s pecific rather than host-specific. At 3 months, hepatocytes in mice we re immunostained with intracellular transforming growth factor (TGF) b eta 1 (LC 1-30) but not with TGF-beta 1 latency-associated peptide (LA P) protein (266-278); at 12 months, hepatocytes were immunostained wit h TGF-beta 1 LAP (266-278) but not with TGF-beta 1 (LC1-30). The hepat ocytes 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 expr ess TGF-beta 1 LAP (266-278) and LC (1-30) proteins, but these were de tected in the cells of the adenoma in the same liver. Control animals showed no hepatic lesions nor immunoreactivity to TGF-beta 1, The spat ial 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.