Chemokine Receptors in MRI Contrast-Induced Organ Fibrosis

描述（由申请人提供）：暴露于基于钆的磁共振成像（MRI）造影剂是获得肾源性系统性纤维化（NSF）的主要危险因素，NSF是一种严重衰弱性疾病，首先在急性或慢性肾损害患者中被发现。迄今为止，MRI造影剂在这些患者中被认为是安全的，因此不加区分地使用。基于钆的造影剂仍然是磁共振成像的主流，替代品仍然缺乏。该建议的总体目标是确定在肾功能不全的情况下，暴露于基于钆的MRI对比后触发异常纤维化模式的候选机制。核心假设是，在真正功能不足的情况下，MRI对比暴露会触发靶器官（如皮肤）的促纤维化状态。随后产生的特异性趋化因子激活并招募骨髓源性和循环间充质前体细胞或纤维细胞到受累区域。这些细胞通过合成和减少细胞外基质的产生以及诱导驻留细胞的增殖来复合纤维化过程。实验将解决以下具体目标：1a，确定钆基造影剂诱导NSF的机制。1b，证明钆造影剂诱导循环纤维细胞增加。确定趋化因子和受体负责募集骨髓源性细胞到特定组织。对NSF的抗性将在CCR2基因缺陷的动物中进行检测。2b，验证钆在正常肾功能和肾功能不全小鼠和大鼠体内的生物分布不同的假设。导致循环细胞向NSF病变募集的化学介质尚未得到很好的探索。这一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会成为目标。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.