title: Stimulation of fibroblast proliferation by insoluble gadolinium salts.
abstract: The purpose of this study was to assess insoluble salts containing gadolinium (Gd(3+)) for effects on human dermal fibroblasts. Responses to insoluble Gd(3+) 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 Gd(3+) phosphate or Gd(3+) carbonate rapidly attached to the fibroblast cell surface and stimulated proliferation. Growth was observed at Gd(3+) 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 Gd(3+) salts was inhibited in the presence of antagonists of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways (similar to chelated Gd(3+)) but was not blocked by an antibody to the platelet-derived growth factor receptor (different from chelated Gd(3+)). Finally, high concentrations of the insoluble Gd(3+) salts failed to prevent fibroblast lysis under low-Ca(2+) conditions, while similar concentrations of chelated Gd(3+) were effective. In conclusion, while insoluble Gd(3+) 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.
authors: Department of Pathology, University of Michigan, 1301 Catherine Road/Box 5602, Ann Arbor, MI 48109, USA.
authors: Katherine
authors: K
authors: Bleavins
authors: Patricia
authors: P
authors: Perone
authors: Madhav
authors: M
authors: Naik
authors: Muneeb
authors: M
authors: Rehman
authors: Muhammad N
authors: MN
authors: Aslam
authors: Michael K
authors: MK
authors: Dame
authors: Sasha
authors: S
authors: Meshinchi
authors: Narasimharao
authors: N
authors: Bhagavathula
authors: James
authors: J
authors: Varani
mesh_terms: D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003287:Contrast Media / Q000009:adverse effects / Q000494:pharmacology*; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005682:Gadolinium / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D012492:Salts / Q000009:adverse effects / Q000494:pharmacology*; D012995:Solubility
chemical_list: D003287:Contrast Media; D012492:Salts; D005682:Gadolinium; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium