Immunohistochemical study of fibrosis and adenocarcinoma in dominant-negative p53 transgenic mice exposed to chrysotile asbestos and benzo(a)pyrene.
We evaluated the mechanisms using immunohistochemistry whereby chrysotile asbestos and benzo(a)pyrene (BaP) instilled intratracheally into lung-specific dominant-negative p53 (dnp53) mice might interact in causing lung carcinomas and fibrosis. Chrysotile asbestos and benzo(a)pyrene (BaP) were instilled intratracheally into lung-specific dominant-negative p53 (dnp53) and control mice. The mice were sacrificed at 12 months and their lungs examined for lung carcinomas and fibrosis. Immunostains for proteins related to apoptosis, fibrogenesis, matrix remodeling and inflammation were performed. The dnp53 mice had increased numbers of lung adenocarcinomas with BaP alone and the combination of chrysotile and BaP (the latter was additive but not significant). Several atypical adenomatous hyperplasia lesions were found in the combined treatment group. dnp53 and FVBN control mice developed nodular buds of fibrotic lung tissue after chrysotile asbestos exposure that were localized in respiratory bronchioles; these lesions had significant increases in immunohistochemical staining for TGF-beta, MMP-7 and -9, MIG-1, and SDF-1. Fibrotic lesions in mice exposed to chrysotile had increased collagen demonstrated by picrosirius red staining. The dnp53 mice with adenocarcinomas had increased SDF-1, TGF-beta, MMP-9 and -7, Cyclin D, and MIG-1 immunostaining in the chrysotile and combined treatment groups. We conclude that BaP and the combination of BaP plus chrysotile asbestos are potent inducers of adenocarcinoma in dnp53 mice and that the inflammatory cytokines and proteases MMP-7 and -9, MIG-1, and SDF-1, and growth factors Cyclin D and TGF-beta are increased in the specific lesions.
Yee
Herman
H
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
Yie
Ting-An
TA
Goldberg
Judith
J
Wong
Kam Meng Tchou
KM
Rom
William N
WN
D000230:Adenocarcinoma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017632:Asbestos, Serpentine / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D007150:Immunohistochemistry; D019570:Inhalation Exposure; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
D017632:Asbestos, Serpentine; D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D053148:Caspase 3; D020782:Matrix Metalloproteinases