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Biological Trace Element Research

, Volume 145, Issue 2, pp 257–267 | Cite as

Stimulation of Fibroblast Proliferation by Insoluble Gadolinium Salts

  • Katherine Bleavins
  • Patricia Perone
  • Madhav Naik
  • Muneeb Rehman
  • Muhammad N. Aslam
  • Michael K. Dame
  • Sasha Meshinchi
  • Narasimharao Bhagavathula
  • James VaraniEmail author
Article

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.

Keywords

Gadolinium phosphate Gadolinium carbonate Gadolinium-based contrast agent Dermal fibroblast Intracellular signaling Proliferation 

Notes

Acknowledgments

This study was supported in part by grant CA140760 from the National Institutes of Health, Bethesda, MD, USA and by grant 11–0577 from the Agency for International Cancer Research.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Katherine Bleavins
    • 1
  • Patricia Perone
    • 1
  • Madhav Naik
    • 1
  • Muneeb Rehman
    • 1
  • Muhammad N. Aslam
    • 1
  • Michael K. Dame
    • 1
  • Sasha Meshinchi
    • 1
    • 2
  • Narasimharao Bhagavathula
    • 1
  • James Varani
    • 1
    Email author
  1. 1.Department of PathologyUniversity of MichiganAnn ArborUSA
  2. 2.Cell and Developmental Biology, Microscopy and Image-Analysis LaboratoryUniversity of MichiganAnn ArborUSA

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