Effects of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents on Human Skin in Organ Culture and Human Skin Fibroblasts

Abstract

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.

Mechanism of NSF: New evidence challenging the prevailing theory

“…4. Dependent edema/fluid overload leading to enhanced exposure of interstitial tissue to GBCA in vivo (6) accords with the observation that fibroblasts can elicit a profibrotic response to GBCA in vitro (40)(41)(42). …”

“…In a separate study, chelated Gd in the form of Omniscan, Magnevist, MultiHance, and ProHance all increased proliferation of human dermal fibroblasts in monolayer culture (41). Additionally, increased proliferation of cells was accompanied by an increase in production of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) but no increase in type I procollagen (41,42). Specific analysis of the signaling events immediately after GBCA application shows activation of tyrosine kinases within minutes following GBCA exposure, again suggesting that chelated Gd could be acting as the trigger molecule (42).…”

“…NSF fibroblasts cultured from the lesions of six NSF patients, all of whom were exposed to Omniscan, synthesized excess levels of hyaluronan and collagen compared to control fibroblasts. In a separate study, chelated Gd in the form of Omniscan, Magnevist, MultiHance, and ProHance all increased proliferation of human dermal fibroblasts in monolayer culture (41). Additionally, increased proliferation of cells was accompanied by an increase in production of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) but no increase in type I procollagen (41,42).…”

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

“…ligand itself without Gd 3þ did not induce skin lesions, and incubation with a ligand also did not induce fibroblast proliferation in vitro (11,16,25). These preclinical data suggest that neither skin lesions nor fibroblast proliferation are related to the presence of free ligand but are, instead, correlated with high Gd concentration in the skin.…”

“…It has also been reported that GBCA exposure in ex vivo skin from healthy humans increases fibroblast proliferation and has effects on the enzyme/inhibitor system that regulates collagen turnover in the skin, in particular an activation of tissue inhibitor of metalloproteinase 1 (TIMP1) and matrix metalloproteinase-1 (MMP-1) (25). The researchers observed an inverse relationship between compound stability and concentration required to stimulate fibroblast responses (25). An in vitro activation of fibroblasts and peripheral blood monocytes by GBCAs have also been reported (26,27).…”