Chemokine Receptors in MRI Contrast-Induced Organ Fibrosis

描述(由申请人提供)：暴露在基于Gd的磁共振成像(MRI)造影剂中是导致肾源性系统性纤维化(NSF)的主要风险因素，NSF是一种最初在急性或慢性肾损害患者中发现的严重衰弱疾病。到目前为止，MRI造影剂在这些患者中被认为是安全的，因此不加区别地使用。基于Gd的造影剂仍然是磁共振成像的中流砥柱，仍然缺乏替代品。这项建议的总体目标是确定在肾功能不全的情况下，暴露于基于Gd的MRI造影剂后，触发纤维化异常模式的候选机制。中心假设是，在真实功能不足的情况下，MRI对比度暴露会触发目标器官(如皮肤)的促纤维化状态。随后产生的特定趋化因子激活并招募骨髓来源的和循环中的间充质前体细胞或纤维细胞到受影响的区域。这些细胞通过合成和减少细胞外基质的生成并诱导驻留细胞的增殖来合成纤维化过程。实验将解决以下具体目标。确定基于Gd的造影剂诱发NSF的机制。1B，证明了基于Gd的造影剂诱导循环中纤维细胞的增加。确定负责将骨髓来源的细胞募集到特定组织的趋化因子和受体。对NSF的抵抗力将在具有CCR2基因缺陷的动物身上进行检测。2B，测试Gd在小鼠和大鼠肾功能正常和肾功能不全之间的生物分布不同的假设。导致循环细胞向NSF皮损募集的化学介质尚未得到很好的研究。这些发现将有助于更好地理解系统性纤维化是如何发生的，以及为什么某些器官是靶向的。这些将适用于NSF和其他纤维细胞介导的疾病。

DESCRIPTION (provided by applicant): Exposure to gadolinium-based magnetic resonance imaging (MRI) contrast is a major risk factor in the acquisition of nephrogenic systemic fibrosis (NSF), a severely debilitating disease first recognized in patients with acute or chronic renal impairment. MRI contrast agents heretofore were considered safe in these patients and thus indiscriminately used. Gadolinium-based contrast agents remain a mainstay for MR imaging and alternatives are still lacking. The overall objective of this proposal is to identify candidate mechanisms that trigger the aberrant pattern of fibrosis after exposure to gadolinium-based MRI contrast in the setting of renal insufficiency. The central hypothesis is that in the setting of real insufficiency, MRI contrast exposure triggers a pro-fibrotic state in target organs, such as the skin. Subsequent generation of specific chemokines activate and recruit bone marrow-derived and circulating mesenchymal precursor cells, or fibrocytes, to the affected areas. These cells compound the fibrotic process by synthesizing and reducing the generation of extracellular matrix and inducing the proliferation of resident cells. Experiments will address the following Specific Aims. 1a, Determine the mechanism by which gadolinium-based contrast induces NSF. 1b, Demonstrate that gadolinium-based contrast induces an increase in circulating fibrocytes. 2a, Identify the chemokines and receptors responsible for recruitment of bone marrow-derived cells to specific tissues. Resistance to NSF will be examined in animals with a genetic deficiency CCR2. 2b, Test the hypothesis that biodistribution of gadolinium differs between normal renal function and renal insufficiency in mice and rats. The chemical mediators that lead to the recruitment of circulating cells to NSF lesions are not well-explored. The findings will lea to a better understanding of how systemic fibrosis occurs and why certain organs are targeted. These will be applicable to NSF and other fibrocyte-mediated ailments.