title: Collagenolytic activity is suppressed in organ-cultured human skin exposed to a gadolinium-based MRI contrast agent.
abstract: OBJECTIVE
  Human skin produces increased amounts of matrix metalloproteinase-1 (MMP-1) when exposed in organ culture to Omniscan, one of the gadolinium-based MRI contrast agents (GBCA). MMP-1, by virtue of its ability to degrade structural collagen, contributes to collagen turnover in the skin. The objective of the present study was to determine whether collagenolytic activity was concomitantly up-regulated with increased enzyme.
  
  
  METHODS
  Skin biopsies from normal volunteers were exposed in organ culture to Omniscan. Organ culture fluids obtained from control and treated skin were examined for ability to degrade type I collagen. The same culture fluids were examined for levels of MMP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and complexes of MMP-1 and TIMP-1.
  
  
  RESULTS
  Although MMP-1 was increased in culture fluid from Omniscan-treated skin, there was no increase in collagenolytic activity. In fact, collagenolytic activity declined. Increased production of TIMP-1 was also observed in Omniscan-treated skin, and the absolute amount of TIMP-1 was greater than the amount of MMP-1. Virtually all of the MMP-1 was present in MMP-1-TIMP-1 complexes, but the majority of TIMP-1 was not associated with MMP-1. When human dermal fibroblasts were exposed to TIMP-1 (up to 250 ng/mL), no increase in proliferation was observed, but an increase in collagen deposition into the cell layer was seen.
  
  
  CONCLUSIONS
  Gadolinium-based MRI contrast agent exposure has recently been linked to a fibrotic skin condition in patients with impaired kidney function. The mechanism is unknown. The increase in TIMP-1 production and concomitant reduction in collagenolytic activity demonstrated here could result in decreased collagen turnover and increased deposition of collagen in lesional skin.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Perone
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Weber
authors.forename: Marissa
authors.initials: M
authors.lastname: DaSilva
authors.forename: Tejaswi
authors.initials: T
authors.lastname: Paruchuri
authors.forename: Narasimharao
authors.initials: N
authors.lastname: Bhagavathula
authors.forename: Muhammad N
authors.initials: MN
authors.lastname: Aslam
authors.forename: Michael K
authors.initials: MK
authors.lastname: Dame
authors.forename: Kent J
authors.initials: KJ
authors.lastname: Johnson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Swartz
authors.forename: James
authors.initials: J
authors.lastname: Varani
mesh_terms: D003094:Collagen / Q000187:drug effects / Q000378:metabolism*; D003287:Contrast Media / Q000494:pharmacology; D015536:Down-Regulation; D005682:Gadolinium / Q000494:pharmacology; D019786:Gadolinium DTPA / Q000494:pharmacology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009924:Organ Culture Techniques; D012867:Skin / Q000187:drug effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D003287:Contrast Media; D019715:Tissue Inhibitor of Metalloproteinase-1; C064925:gadodiamide; D003094:Collagen; D005682:Gadolinium; D020781:Matrix Metalloproteinase 1; D019786:Gadolinium DTPA