Stimulation of Fibroblast Proliferation by Insoluble Gadolinium Salts

Abstract

The purpose of this study was to assess insoluble salts containing gadolinium (Gd3+) for effects on human dermal fibroblasts. Responses to insoluble Gd3+ salts were compared to responses seen with Gd3+ solubilized with organic chelators, as in the Gd3+-based contrast agents (GBCAs) used for magnetic resonance imaging. Insoluble particles of either Gd3+-phosphate or Gd3+-carbonate rapidly attached to the fibroblast cell surface and stimulated proliferation. Growth was observed at Gd3+ concentrations between 12.5 and 125 μM, with toxicity at higher concentrations. Such a narrow window did not characterize GBCA stimulation. Proliferation induced by insoluble Gd3+ salts was inhibited in the presence of antagonists of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways (similar to chelated Gd3+) but was not blocked by an antibody to the platelet-derived growth factor receptor (different from chelated-Gd3+). Finally, high concentrations of the insoluble Gd3+ salts failed to prevent fibroblast lysis under low-Ca2+ conditions while similar concentrations of chelated-Gd3+ were effective. In conclusion, while insoluble Gd3+ salts are capable of stimulating fibroblast proliferation, one should be cautious in assuming that GBCA dechelation must occur in vivo to produce the profibrotic changes seen in association with GBCA exposure in the subset of renal failure patients that develop nephrogenic systemic fibrosis.

Growth Control in Colon Epithelial Cells: Gadolinium Enhances Calcium-Mediated Growth Regulation

“…Since gadolinium rapidly forms insoluble precipitates with phosphate, carbonate, and other anions in biological fluids [32], experiments were conducted in which a chelated gadolinium compound (Magnevist; i.e., gadolinium diethylenetriaminepentaacetic acid N -methylglucamine) was used in place of gadolinium chloride. Similar to what we observed with gadolinium chloride, the chelated gadolinium compound (250 and 500 µM) induced a decrease in the number of colon epithelial cells when combined with millimolar amounts of calcium (Fig.…”

“…Previous studies have shown that gadolinium interferes with receptor-gated calcium channels, as well as voltage-gated and mechanical stress-activated channels in a variety of cells [22, 24, 36, 37]. While some studies have suggested that limiting the rise in intracellular calcium might prevent apoptosis and promote cancer development, most studies have demonstrated that blocking calcium movement into the cell induces cell death [reviewed in 32]. In the colon epithelial cells studied here, interference with calcium movement is clearly associated with reduced cell growth.…”

Gadolinium Compounds Signaling through TLR 4 and TLR 7 in Normal Human Macrophages: Establishment of a Proinflammatory Phenotype and Implications for the Pathogenesis of Nephrogenic Systemic Fibrosis

“…Once phagocytosed, Omniscan ® would be able to amplify its TLR signaling capacity by engaging TLR7 within the endosome. Several reports of Gd deposits found in affected tissues from NSF patients described the presence of macrophages in close proximity (9–12), suggesting that the highly acidic environment of the endosome could facilitate deposition of Gd salts, such as Gd phosphate and Gd carbonate (49). These precipitated Gd salts could then maintain a constant state of TLR activation in both macrophages and fibroblasts, producing a chronic proinflammatory/profibrotic phenotype responsible for disease persistence and progression.…”

Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model

“…Linear GBCAs have higher dissociation rates than macrocyclic GBCAs; the resulting free Gd may bind to endogenous molecules such as phosphate, carbonate or macromolecules, leading to Gd retention in various tissues. 10,11 In the unchelated form, Gd is highly toxic and may cause splenic and lung degeneration or liver necrosis.…”