INVESTIGATION OF GADOLINIUM CONTRAST AGENT TOXICITY BY X-RAY FLUORESCENCE MICROS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由于它们的顺磁性，有机Gd配合物和Gd化合物的溶液被用作静脉注射放射造影剂，以增强医学磁共振成像中的图像。多年来，美国、欧洲和日本的成年人和儿童一直在使用Gd，数千名患者没有出现任何严重的并发症。美国食品和药物管理局于1988年宣布，在核磁共振中使用Gd是安全的。肾源性系统性纤维化，或称NSF，是一种相对较新的疾病，专家认为与使用基于Gd的造影剂有关。美国食品和药物管理局于2006年6月首次提醒医学界和公众注意这一联系，然后在12月再次提醒。2007年5月，该机构要求更新基于Gd的MRI染料的标签，以包括患有肾脏疾病或功能不全的患者患NSF的风险。NSF是一种高度虚弱，有时甚至是致命的硬皮病样疾病，发生在严重或终末期肾功能衰竭的患者中。虽然目前尚不清楚这种疾病的分子起源，但NSF和Gd MRI造影剂之间的联系在于观察到相当数量的Gd沉积在NSF患者的各种器官中，包括心脏、肾脏和肝脏(1)，以及皮肤病变(2)。关于Gd在这些患者中的毒性机制，已经提出了许多假说(3)，大多数假说认为Gd3+从其有机螯合配体中释放出来，并随后与周围环境中的Gd3+相互作用。预先存在的肾功能衰竭可能通过延迟Gd造影剂的排泄来促进这些过程。对Gd如何与NSF患者的组织相互作用的基本了解将对确定Gd在这种疾病的分子起源中所起的作用至关重要。要了解Gd诱导NSF的机制，关键的第一步是了解Gd的详细分布。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Because of their paramagnetic properties, solutions of organic gadolinium complexes and gadolinium compounds are used as intravenous radiocontrast agents to enhance images in medical magnetic resonance imaging. Gadolinium has been used for years in adults and children in the United States, Europe and Japan, without any serious complications in thousands of patients. The FDA declared gadolinium safe for use in MRI in 1988. Nephrogenic systemic fibrosis, or NSF, is a relatively new disease that experts have linked to the use of gadolinium-based contrast agents. The Food and Drug Administration first alerted the medical community and public about this link in June 2006, then again in December. In May 2007, the agency asked that the labeling of gadolinium-based MRI dyes be updated to include the risk of NSF in patients with kidney disease or insufficiencies. NSF is a highly debilitating and sometimes fatal scleroderma-like disease that occurs within patients with severe or end-stage renal failure. Though the molecular origin of the disease is currently not known, the connection between NSF and gadolinium MRI contrast agents lies in the observation that appreciable amounts of Gd have been found deposited in various organs, including the heart, kidneys, and liver (1), and in skin lesions (2) of NSF patients. Many hypotheses have been put forward regarding the mechanism of Gd toxicity in these patients (3) and the majority proposes the release of Gd3+ from its organic chelating ligand and subsequent interactions with Gd3+ the surrounding milieu. Preexisting renal failure may facilitate these processes by delaying the excretion of the Gd contrast agents. A fundamental understanding of how Gd interacts with tissues of NSF patients will be crucial in determining the role Gd plays in the molecular origins of this disease. A critical first step towards understanding the mechanism of Gd- induced NSF is understanding the detailed distribution of Gd.