Effects of gadolinium-based magnetic resonance imaging contrast agents on human skin in organ culture and human skin fibroblasts.
OBJECTIVE
Nephrogenic systemic fibrosis (NSF) is a clinical syndrome linked with exposure in renal failure patients to gadolinium-based magnetic resonance imaging contrast agents (GBCAs). The pathogenesis of the disease is largely unknown. The present study addresses potential pathophysiological mechanisms.


METHODS
Here, we have examined human skin in organ culture and human dermal fibroblasts in monolayer culture for responses to GBCA stimulation.


RESULTS
Treatment of normal human skin in organ culture with Omniscan had no significant effect on type I procollagen but increased both matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1. At the histologic level, many interstitial cells demonstrated cytologic features characteristic of activation (ie, light staining, oblong, plump nuclei). Omniscan, as well as 3 other magnetic resonance imaging contrast agents (Magnevist, Multihance, and Prohance), increased proliferation of human dermal fibroblasts in monolayer culture. Increased proliferation was accompanied by an increase in production of both matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 but no increase in type I procollagen. Concentrations required for effects differed among the 4 agents (Omniscan < Magnevist and Multihance < Prohance). In contrast to its effects on fibroblast function, Omniscan did not stimulate human epidermal keratinocyte proliferation when examined over a wide range of concentrations.


CONCLUSIONS
These data provide evidence that GBCA exposure in ex vivo skin from healthy individuals increases fibroblast proliferation and has effects on the enzyme/inhibitor system that regulates collagen turnover in the skin.
Varani
James
J
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. varani@umich.edu
DaSilva
Marissa
M
Warner
Roscoe L
RL
Deming
Monica O'Brien
MO
Barron
Adam G
AG
Johnson
Kent J
KJ
Swartz
Richard D
RD
D000293:Adolescent; D000368:Aged; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003287:Contrast Media / Q000008:administration & dosage; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005682:Gadolinium / Q000008:administration & dosage*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D009924:Organ Culture Techniques; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
D003287:Contrast Media; D016326:Extracellular Matrix Proteins; D005682:Gadolinium