Fibroblast response to gadolinium: role for platelet-derived growth factor receptor.
OBJECTIVE
The purpose of this study was to assess the effects of gadolinium (Gd3+), provided as gadolinium chloride, on fibroblast function.


METHODS
Human dermal fibroblasts in monolayer culture and intact skin in organ culture were exposed to the lanthanide metal (1-20 μM).


RESULTS
Increased proliferation was observed, in association with upregulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1, without an apparent increase in production of type I procollagen. A platelet-derived growth factor (PDGF) receptor-blocking antibody inhibited fibroblast proliferation in response to Gd3+ as did inhibitors of signaling pathways--that is, mitogen-activated protein kinase and phosphatidylinositol-3 kinase pathways--that are activated by PDGF.


CONCLUSIONS
The responses to gadolinium chloride are similar to responses previously seen with chelated Gd3+ in clinically used magnetic resonance imaging contrast agents. Fibroblast responses appear to reflect Gd3+-induced PDGF receptor activation and downstream signaling. Increased dermal fibroblast proliferation in conjunction with effects on matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 could contribute to the fibroplastic/fibrotic changes seen in the lesional skin of individuals with nephrogenic systemic fibrosis.
Bhagavathula
Narasimharao
N
Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA.
Dame
Michael K
MK
DaSilva
Marissa
M
Jenkins
William
W
Aslam
Muhammad N
MN
Perone
Patricia
P
Varani
James
J
D000704:Analysis of Variance; D001706:Biopsy; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003287:Contrast Media / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology*; D019786:Gadolinium DTPA / Q000494:pharmacology; D006801:Humans; D049449:Luminescence; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation
D003287:Contrast Media; D011347:Procollagen; D019715:Tissue Inhibitor of Metalloproteinase-1; C064925:gadodiamide; D005682:Gadolinium; D017479:Receptors, Platelet-Derived Growth Factor; D020928:Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D019786:Gadolinium DTPA; C038958:gadolinium chloride