Type of MRI contrast, tissue gadolinium, and fibrosis

Abstract

It has been presupposed that the thermodynamic stability constant ( Ktherm) of gadolinium-based MRI chelates relate to the risk of precipitating nephrogenic systemic fibrosis. The present study compared low- Ktherm gadodiamide with high- Ktherm gadoteridol in cultured fibroblasts and rats with uninephrectomies. Gadolinium content was assessed using scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy in paraffin-embedded tissues. In vitro, fibroblasts demonstrated dose-dependent fibronectin generation, transforming growth factor-β production, and expression of activated myofibroblast stress fiber protein α-smooth muscle actin. There were negligible differences with respect to toxicity or proliferation between the two contrast agents. In the rodent model, gadodiamide treatment led to greater skin fibrosis and dermal cellularity than gadoteridol. In the kidney, both contrast agents led to proximal tubule vacuolization and increased fibronectin accumulation. Despite large detectable gadolinium signals in the spleen, skin, muscle, and liver from the gadodiamide-treated group, contrast-induced fibrosis appeared to be limited to the skin and kidney. These findings support the hypothesis that low- Ktherm chelates have a greater propensity to elicit nephrogenic systemic fibrosis and demonstrate that certain tissues are resistant to these effects.

Pathophysiology of gadolinium-associated systemic fibrosis

“…When quiescent human foreskin fibroblasts are treated with a clinically relevant dose of gadodiamide (0.2 mM), they exhibit ␣-smooth muscle actin stress fibers in addition to an accumulation of fibronectin, a correlate of extracellular matrix accumulation. These doses of contrast do not elicit a very robust proliferative or toxic effect (26).…”

“…The measurements of the ligand-gadolinium affinities are expressed in terms of "thermodynamic stabilities," K therm (26):…”

“…F: animals that received tempol demonstrated less oxidative stress than those subjected to magnetic resonance contrast alone. many of the metal-laden organs (other than the kidney) (26). Because the liver should be a sink for liberated gadolinium, yet remains histologically intact, perhaps there is an antifibrotic mechanism that is specific to this and other organs.…”

The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro

“…This may lead to nephrogenic systemic fibrosis in patients suffering from renal insufficiency. [14][15][16][17] Thus, a testing of these compounds for cytotoxicity and their inflammatory potential is indispensable. The effects of Ba/Gd were examined in the model representing the "healthy" in vitro barrier, and with the model representing an "inflamed barrier", in which the coculture was first exposed to a proinflammatory cytokine mixture (TNF-α, INF-γ, IL1-β) prior to the addition of Ba/Gd.…”

In vivo assay of the potential gadolinium‐induced toxicity for sensory hair cells using a zebrafish animal model

“…Acute neurotoxicity, such as myoclonus, ataxia or tremor, has been observed in rats after gadolinium administration (Ray, Cavanagh, Nolan, & Williams, ). Various pathological changes have also been observed, including apoptosis, necrosis, induction of fibrotic chemokines and cytokines, elevation of reactive oxygen species (ROS) and mitochondrial damage (Chen et al, ; Do, Barnes, Tan, & Wagner, ; Heinrich et al, ; Jin, Chen, Duan, Jia, & Zhang, ; Mizgerd, Molina, Stearns, Brain, & Warner, ; Xia et al, ). Our results confirmed an increase in apoptosis (TUNEL assay) and a decreased mitochondrial viability (DASPEI assay) upon the exposure to high concentrations of GdC.…”