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Gadolinium induces macrophage apoptosis
J P Mizgerd1, R M Molina, R C Stearns
1Physiology Program, Harvard School of Public Health, Boston, MA 02115, USA.
Abstract:
Gadolinium (Gd) suppresses reticuloendothelial functions in vivo by unknown mechanisms. In vitro exposure of rat alveolar macrophages to GdCl3.6H20 caused cell death, as measured by trypan blue permeability, in both dose- and time-dependent fashions. Even a 10-min exposure to Gd caused significant cell death by 24 h. The morphology of Gd-treated cells, pyknosis and karyorrhexis prior to loss of membrane integrity, suggested apoptosis. Upon flow cytometric examination, Gd-treated propidium iodide-excluding cells demonstrated light scatter changes characteristic of apoptotic cells (decreased forward and increased right angle scatter). Gel electrophoresis of DNA from Gd-treated macrophages clearly showed the ladder pattern unique to apoptotic cells. Electron-dense structures containing Gd were observed via electron spectroscopic imaging within phagosomes and also within nuclei (associated with condensed chromatin). Gadolinium, endocytosed by macrophages and distributed to nuclei, causes apoptosis of macrophages in vitro.
Insights
Gadolinium exposure induces apoptosis in rat macrophages. This metal is endocytosed, reaching cell nuclei and triggering programmed cell death via unknown mechanisms, impacting reticuloendothelial functions.
Area of Science:
- Immunology
- Cell Biology
- Toxicology
Background:
- Gadolinium (Gd) is known to suppress reticuloendothelial functions in vivo.
- The precise mechanisms underlying this suppression remain largely unknown.
Purpose of the Study:
- To investigate the in vitro effects of Gadolinium chloride hexahydrate (GdCl3·6H2O) on rat alveolar macrophages.
- To elucidate the cellular mechanisms by which Gd impacts macrophage viability and function.
Main Methods:
- Macrophages were exposed to varying concentrations and durations of GdCl3·6H2O.
- Cell death was assessed using trypan blue permeability.
- Apoptosis was evaluated through flow cytometry (light scatter analysis) and DNA gel electrophoresis.
- Intracellular Gd localization was determined using electron spectroscopic imaging.
Main Results:
- GdCl3·6H2O exposure caused dose- and time-dependent cell death in macrophages.
- Morphological changes (pyknosis, karyorrhexis) and DNA fragmentation indicated apoptosis.
- Flow cytometry revealed apoptotic light scatter patterns in Gd-treated cells.
- Electron spectroscopic imaging detected Gd within phagosomes and nuclei, associated with condensed chromatin.
Conclusions:
- Gadolinium is endocytosed by macrophages and translocated to the nucleus.
- Nuclear accumulation of Gd triggers apoptosis in macrophages in vitro.
- This study provides mechanistic insight into Gd-induced suppression of reticuloendothelial functions.