Forensic and Clinical Toxicology Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.
Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Contrast Media Mol Imaging. 2018 Dec 2;2018:3535769. doi: 10.1155/2018/3535769. eCollection 2018.
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 mol/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-1 secretion and IL-6 and IL-10 secretion. Moreover, upon LPS stimulation, there is decreased TNF- secretion 4 hours after Primovist® or Omiscan® exposure but the TNF- 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 animal study may clarify the role of macrophage on the pathogenesis of NSF and other GBCAs-related disease.
钆基造影剂（GBCA）的毒性引起了广泛关注。肾源性系统性纤维化（NSF）是一种与 GBCA 使用相关的致命疾病，但目前仍未得到充分认识。最近，在磁共振成像（MRI）中反复使用 GBCA 后，发现脑组织中存在钆的蓄积。然而，大多数研究 GBCA 毒性的工作都集中在其高浓度（0.5-10mM）部分，而这并不反映人体的生理状况。巨噬细胞在免疫反应中发挥调节作用，并负责纤维化过程。然而，它们在 GBCA 蓄积和 NSF 发病机制中的作用很少被研究。本研究旨在评估巨噬细胞（RAW 264.7）暴露于低浓度 GBCA 时产生的免疫反应。通过电感耦合等离子体质谱法（ICP-MS）检测和 MRI 成像，GBCA 的孵育浓度与通过 GBCA 摄取的钆水平成正比，而在所有测试浓度中，普美显®处理组的钆摄取量最高。低浓度（2.5mol/L）Gd 氯化物或 GBCA 暴露会促进活性氧（ROS）、硝酸盐/亚硝酸盐、前列腺素 E2（PGE2）的产生，并抑制线粒体膜的潜能。与 Gadovist®组相比，普美显®、欧乃影®和马根维显®组的 ROS、硝酸盐/亚硝酸盐和 PGE2 产生更高。在脂多糖（LPS）刺激下，普美显®、欧乃影®和马根维显®组的亚硝酸盐/硝酸盐和抑制白细胞介素 1（IL-1）分泌和白细胞介素 6（IL-6）和白细胞介素 10（IL-10）分泌增加。此外，在 LPS 刺激下，普美显®或欧乃影®暴露 4 小时后 TNF-分泌减少，但 24 小时后 TNF-分泌增加。我们的数据表明，即使存在低浓度的 GBCA，也会引起炎症反应上调，甚至类似于鼠巨噬细胞的生理状态。进一步研究 GBCA 对人巨噬细胞或动物的影响，可能会阐明巨噬细胞在 NSF 和其他 GBCA 相关疾病发病机制中的作用。
