title: Effects of magnetic resonance imaging contrast agents on human umbilical vein endothelial cells and evaluation of magnetic resonance imaging contrast media-triggered transforming growth factor-beta induction in dermal fibroblasts (HSF) as a model for nephrogenic systemic fibrosis.
abstract: OBJECTIVE
  The objective of this study was to evaluate effects of 6 commercially available magnetic resonance contrast media (CM) on human umbilical vein endothelial cells (HUVEC) and the induction of transforming growth factor-beta (TGF-β) in dermal fibroblasts (HSF) as a possible model for the pathogenesis of nephrogenic systemic fibrosis.
  
  
  METHODS
  HUVECs were incubated with 10× and 20× of the molar standard blood concentration achieved with CM applications for magnetic resonance imaging examinations (10× and 20× concentration) for 24 hours using gadolinium-based CM Gadovist, Magnevist, Multihance, and Omniscan, as well as Teslascan (Manganese-based), and Resovist (Iron-based). Proliferation kinetics (PK), colony formation, and viability assays were performed. Additionally, human dermal fibroblasts (HSF) were incubated for 24 hours with 1× and 20× concentration in all 6 CM, and TGF-β levels were assessed directly after the incubation period as well as on days 3 and 8 postincubation.
  
  
  RESULTS
  HUVEC PK data show similar gains in cell numbers for all 6 CM in both concentration groups over the 17-day assessment period. Only cells incubated with Omniscan and Teslascan differed from the other groups on days 3 and 7 postincubation (P < 0.05). After day 7, a cell regain occurred in the Omniscan and Teslascan groups reaching the numbers of the other groups in sequel. Differences in colony formation were consistent with PK results with a statistically significant reduction in clonogenic activity for Teslascan and Omniscan in HUVEC cells, P < 0.05. No reduction in viability was seen for all groups and conditions. TGF-β expression of HSF cells incubated with 1× concentration and all CM did not differ significantly from control cells for any point in time investigated. At 20× concentration directly after incubation, TGF-β was significantly reduced for the Teslascan and Resovist group as 3 compared with control and all other CM groups, P < 0.05. On day 3 postincubation, only Resovist-incubated HSF cells showed a significant reduction of TGF-β (1.614, standard deviations: 89) as compared with the control group (2.883, standard deviations: 30) and the other CM. TGF-β was slightly reduced for all CM groups 8 days after incubation (not statistically significant, P > 0.05).
  
  
  CONCLUSIONS
  After 24 hours of incubation with Omniscan and Teslascan (10× and 20× concentration), considerable short-term antiproliferative effects in HUVECs were observed. HSF cells (20× concentration) showed a reduction of TGF-β for Resovist and Teslascan directly after incubation, whereas TGF-β levels in HSF cells were slightly reduced for all CM 8 days after incubation. Therefore, TGF-β-mediated proliferative effects on fibroblasts or on collagen synthesis potentially leading to nephrogenic systemic fibrosis may mainly be triggered by tissue monocytes and macrophages in the peripheral blood instead of dermal fibroblasts.
authors.affiliation: Department of Diagnostic Radiology, University of Tuebingen, Tuebingen, Germany. benjamin.wiesinger@med.uni-tuebingen.de
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wiesinger
authors.forename: Rainer
authors.initials: R
authors.lastname: Kehlbach
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hemsen
authors.forename: Julie
authors.initials: J
authors.lastname: Bebin
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Bantleon
authors.forename: Nina
authors.initials: N
authors.lastname: Schwenzer
authors.forename: Daniel
authors.initials: D
authors.lastname: Spira
authors.forename: Claus D
authors.initials: CD
authors.lastname: Claussen
authors.forename: Jakub
authors.initials: J
authors.lastname: Wiskirchen
mesh_terms: D003094:Collagen; D003287:Contrast Media / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000166:cytology*; D005347:Fibroblasts / Q000187:drug effects; D019786:Gadolinium DTPA / Q000009:adverse effects; D006801:Humans; D007118:Immunoassay; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D054989:Nephrogenic Fibrosing Dermopathy / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000473:pathology; D011877:Radionuclide Imaging; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D014471:Umbilical Veins / Q000166:cytology*
chemical_list: D003287:Contrast Media; D053773:Transforming Growth Factor beta1; D003094:Collagen; D019786:Gadolinium DTPA