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 Gd 3+ solubilized with organic chelators, as in the Gd 3+-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. © 2011 Springer Science+Business Media, LLC.