Exposure of Macrophages to Low-Dose Gadolinium-Based Contrast Medium: Impact on Oxidative Stress and Cytokines Production

Abstract

The toxicity of gadolinium-based contrast agents (GBCAs) has drawn a lot of attention. Nephrogenic systemic fibrosis (NSF), a lethal disease related to the use of GBCAs, is still not understood. Recently, gadolinium retention is found in brain tissues after repeated use of GBCAs in magnetic resonance imaging (MRI). However, most of the works investigating the toxicity of GBCAs are focusing on its high-concentration (0.5–10 mM) part, which is not reflective of the physiological conditions in human beings. Macrophages play a regulatory role in immune responses and are responsible for the fibrosis process. Their role in gadolinium retention and the pathogenesis of NSF, however, has seldom been investigated. This study aimed to evaluate the immune response generated by macrophages (RAW 264.7) exposing to low levels of GBCAs. The incubation concentration of GBCAs, including Omniscan®, Primovist®, Magnevist®, and Gadovist®, is proportional to the level of gadolinium uptake when detected via inductively coupled plasma mass spectrometry (ICP-MS) and imaged by MRI, whereas Primovist® treatment groups have highest gadolinium uptake among all of the tested concentrations. Low-concentration (2.5 μmol/L) Gd chloride or GBCAs exposure promoted the reactive production of oxygen species (ROS), nitrate/nitrite, prostaglandin E2 (PGE2), and suppressed the potential of mitochondrial membrane. There was higher ROS, nitrate/nitrite, and PGE2 production in the Primovist®, Omniscan®, and Magnevist® groups compared to the Gadovist® group. In face of lipopolysaccharide (LPS) stimulation, Primovist®, Omniscan®, and Magnevist® groups exhibited elevated nitrite/nitrate and suppressed IL-1β secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF-α secretion 4 hours after Primovist® or Omiscan® exposure but the TNF-α secretion increased at 24 hours. Our data suggest that there is upregulated inflammation even in the presence of low levels of GBCAs, even similar to the physiological condition in murine macrophage. Further investigation of GBCAs on the human macrophage or in vivo animal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent

“…Treatment of various multiple myeloma cell lines with motexafin gadolinium in the presence of ascorbate increases reactive oxygen species production, decreases mitochondrial membrane potential, and induces apoptosis via induction of annexin V. 40 Likewise, exposing murine macrophages to GBCAs at concentrations as low as 2.5 μM induces mitochondrial stress with reactive oxygen species production and reduced mitochondrial membrane potential and alters inflammatory cytokine production. 41 This study also found greater impairments after treatment with linear agents in comparison to the macrocyclic gadobutrol.…”

Gadolinium Oxide Nanoparticles Induce Toxicity in Human Endothelial HUVECs via Lipid Peroxidation, Mitochondrial Dysfunction and Autophagy Modulation

“…Seo et al [ 60 ] reported the induction of ROS by GO NPs in abiotic aqueous solutions as well. Even ultra-low concentrations (2.5 µM/L) of GdCl 3 salt have been shown to promote the production of ROS and cytokines in RAW 264.7 macrophage cells [ 61 ]. Mitochondrial-membrane potential (MMP) is the manifestation of induced ROS that is often considered a committed step in inducing death activating pathways [ 62 ].…”

Evaluation of toxicity of gadolinium-based contrast agents on neuronal cells

“…Our results are also consistent with a study performed in rat neurons, which found that, within 24 h, gadolinium chloride induces mitochondrial dysfunction and cell death (30). Likewise, exposing murine macrophages to GBCAs at concentrations as low as 2.5 µM induces mitochondrial stress with ROS production and reduced mitochondrial membrane potential and alters inflammatory cytokine production (31). Overall, these results indicate that toxic effects of GBCAs exacerbate depending on the dose and the kinetic stability of the contrast agent.…”