title: Activation of the hexose monophosphate shunt in rat type II pneumocytes as an early marker of oxidative stress caused by cobalt particles.
abstract: Cobalt metal (mCo) and hard metal, a mixture of cobalt and tungsten carbide (CoWC), are cytotoxic for alveolar macrophages and alveolar type II cells (AT-II). Although the exact mechanisms of toxicity are not entirely elucidated, evidence exists for an oxidant-mediated toxicity. In this study, we exposed primary cultures of rat AT-II, in vitro, to different forms of cobalt (mCo particles, CoWC particles, CoCl(2)) and assessed changes in the activity of the hexose monophosphate shunt (HMS). Activation of the HMS occurs as an early response to (per)oxidative stress. Cobalt metal-containing particles (mCo and CoWC) when freshly immersed in medium, lead to an early concentration-dependent stimulation of the HMS in rat AT-II. The maximum stimulations of HMS (reached after 90 min) were 2.0 +/-1.2, 2.9+/-0.4, 3.3 +/-1.6 and 4.0+/-0.4 fold-increases for 15, 75, 300 and 1200 microg mCo/well, respectively. The observed time course of the activation by mCo particles clearly differed from that caused by paraquat (10(-5 )M), which is known to produce activated oxygen species after cyclic oxidation-reduction reactions. The comparable effect of peroxides (H2O2 and t-butyl hydroperoxide) on HMS and the inhibitory effects of catalase on the mCo-induced stimulation of the HMS strongly suggest the production of peroxides by freshly immersed mCo particles. However, we were not able to show a simple relationship between the stimulation of the HMS and the subsequent cell damage.
authors.affiliation: Laboratory of Pneumology (Unit of Lung Toxicology), K.U. Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Hoet
authors.forename: Goedele
authors.initials: G
authors.lastname: Roesems
authors.forename: Maurits G
authors.initials: MG
authors.lastname: Demedts
authors.forename: Benoit
authors.initials: B
authors.lastname: Nemery
mesh_terms: D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D003035:Cobalt / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004391:Dust / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000502:physiology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017973:Tungsten Compounds / Q000633:toxicity; D020122:tert-Butylhydroperoxide / Q000633:toxicity
chemical_list: D015415:Biomarkers; D004338:Drug Combinations; D004391:Dust; D017973:Tungsten Compounds; C002802:tungsten carbide; D003035:Cobalt; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; C018021:cobaltous chloride