Interactions of alpha Ni3S2 with guinea pig alveolar macrophages and liberation of inflammatory mediators.
Our previous investigation presented evidence of interaction between alpha Ni3S2 and membranous and cellular lipids of lung cells, resulting in significant increases in linoleic, linolenic and arachidonic acids. The present work was designed to follow the metabolic fate of arachidonic acid in alpha Ni3S2-exposed guinea pig alveolar macrophages (GPAM) in culture (50 microM alpha Ni3S2 for 3 days). The metabolites of arachidonic acid were assessed by HPLC coupled with UV or electrochemical detection. The concentrations of malondialdehyde (MDA), hydroxyeicosatetraenoic acid (HETE), leukotrienes (LT) and reduced glutathione (GSH) were measured. In exposed cells a significant increase of MDA, a breakdown product of lipid peroxidation, was observed. In addition, the enzymatic reduction of 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by the associated oxidation of GSH to GSSG increased 5-HETE in GPAM cells and decreased GSH. 5-Hydroperoxyeicosatetraenoic acid was furthermore converted to epoxides, such as leukotriene A4, and we also quantified in exposed cells a significant increase of its subsequent catabolites LTB4, LTC4 and LTE4. Direct measurements of MDA and other metabolites of arachidonic acid clearly show that exposure of GPAM cells to alpha Ni3S2 enhances lipid peroxidation. This lipid peroxidation is an autocatalytic free-radical process and could be responsible for DNA damage. Furthermore, alpha Ni3S2 intoxication induces the release of proinflammatory products, such as leukotrienes, and the decrease of glutathione.
Teissier
E
E
U-16 INSERM, Faculté de Médicine, France.
Shirali
P
P
Hannothiaux
M H
MH
Marez
T
T
Haguenoer
J M
JM
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008315:Malondialdehyde / Q000378:metabolism; D009532:Nickel / Q000633:toxicity*
D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D016718:Arachidonic Acid; D008315:Malondialdehyde; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D009532:Nickel; D005978:Glutathione; C017557:nickel subsulfide