Iron-dependent lysosomal destabilization initiates silica-induced apoptosis in murine macrophages.
Alveolar macrophages play a critical role in silica-induced lung fibrosis, and apoptotic mechanisms have been implicated in silica-induced pathogenesis. Here, employing a model of murine macrophages (J774 cells), it is shown that serum-coated alpha-quartz silica particles cause lysosomal rupture and apoptosis following endocytotic uptake. The loss of lysosomal integrity involves intralysosomal iron-catalyzed peroxidative damage to lysosomal membranes. Thus, lysosomal damage is most pronounced in cells exposed to silica particles with high amounts of surface-bound iron, whereas silica particles previously treated with the iron chelator desferrioxamine only induce modest rupture. Furthermore, inhibition of intralysosomal Fenton type chemistry, either by pre-treatment with desferrioxamine complexed to starch--an iron chelator targeted to the lysosomal compartment--or by concomitant treatment with diphenylene iodonium--a potent inhibitor of NADPH oxidase --both prevent silica-induced lysosomal leakage and ensuing apoptotic cell death. This study also demonstrates that silica-induced lysosomal rupture is a very early apoptotic event, preceding activation of caspases, disruption of transmembrane mitochondrial potential and DNA fragmentation. Indeed, these later apoptotic events appear to be directly correlated to the magnitude of lysosomal leakage, and are not observed in cells treated with high molecular weight desferrioxamine or diphenylene iodonium.
Persson
H Lennart
HL
Divisions of Pulmonary Medicine, Faculty of Health Sciences, University of Linköping, SE58185 Linköping, Sweden. Lenpe@inr.liu.se
D000818:Animals; D017209:Apoptosis; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides; D053938:DNA Fragmentation; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009861:Onium Compounds / Q000494:pharmacology; D044967:Serum; D012822:Silicon Dioxide / Q000633:toxicity*
D002712:Chlorides; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D007502:Iron Chelating Agents; D009861:Onium Compounds; C007517:diphenyleneiodonium; D012822:Silicon Dioxide; D019255:NADPH Oxidases; D003676:Deferoxamine; C024555:ferric chloride