Mechanisms of induction of ornithine decarboxylase activity in tracheal epithelial cells by asbestiform minerals.
Asbestos induces a constellation of biological responses in cells of the respiratory tract that are similar to those of classical tumor promoters. In this regard, induction of ornithine decarboxylase (ODC) activity and increased incorporation of [3H]thymidine have been documented after addition of crocidolite and chrysotile asbestos to a hamster tracheal epithelial cell line (J. M. Landesman and B. T. Mossman, Cancer Res., 42:3669-3675, 1982). The objectives of studies here were to determine: (a) the importance of geometry, size, and/or chemical composition of asbestos fibers on induction of ODC activity; and (b) the possible involvement of calcium and/or protein kinase C in asbestos-induced ODC activity. After addition for 24 h to confluent hamster tracheal epithelial cells, fibers of crocidolite, chrysotile, and glass in medium containing fresh serum caused a significant increase in ODC activity. Stimulation of ODC was not observed when nonfibrous analogues (riebeckite, antigorite, and glass particles) were used. Sized preparations of long (greater than 10-micron length) chrysotile fibers were more potent in enhancing ODC activity than shorter (less than or equal to 2-micron length) fibers at similar concentrations. The mechanisms of ODC induction by asbestos were probed by adding the calcium channel blockers (verapamil and nifedipine) and inhibitors [10(-5) to 10(-7)M of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, of N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, of TMB-8, and of palmitoyl carnitine] of protein kinase C simultaneously with chrysotile asbestos. These agents inhibited ODC activity by chrysotile in a dosage-dependent fashion. Results suggest that the fibrous geometry and length of asbestos fibers are critical in initiating ODC activity in airway epithelial cells. Moreover, they implicate the importance of calcium and protein kinase C in asbestos-induced mitogenic responses.
Marsh
J P
JP
Department of Pathology, University of Vermont College of Medicine, Burlington 05405.
Mossman
B T
BT
D000818:Animals; D001194:Asbestos / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004790:Enzyme Induction / Q000187:drug effects*; D004848:Epithelium / Q000201:enzymology; D066298:In Vitro Techniques; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000166:cytology / Q000201:enzymology*
D002121:Calcium Channel Blockers; D001194:Asbestos; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase; D002118:Calcium