Molecular Imaging CCR2 Lung Inflammation and Fibrosis

总结 肺纤维化是一种认识不足、失调的细胞反应的结果，很难诊断 特发性肺纤维化（IPF）是一种常见的形式，具有进行性的下坡过程。没有 用于诊断、治疗或疾病活动的公认的分子生物标志物。临床医生目前依赖于 对胸部计算机断层扫描（CT）和肺功能的变化进行监测。而且 只有两种被批准的药物疗法，并且治疗不受分子生物标志物的指导。肺CCR 2+（C-C 基序趋化因子受体2）炎性单核细胞及其病理性后代，间质巨噬细胞， 与肺纤维化的实验性发展密切相关，在肺纤维化患者的肺中升高， 肺纤维化，并产生促纤维化因子。纤维化在Ccr 2缺失小鼠中显著减弱， CCR 2+子代巨噬细胞的缺失，强烈支持CCR 2+细胞在人类疾病中的作用。这 该提案旨在利用分子，正电子发射断层扫描（PET）为基础的诊断，以检测CCR 2- 介导的炎症的肺纤维化患者，并开发有针对性的治疗。我们 一个多学科小组已经确定，基于肽的放射性示踪剂64 Cu-DOTA-ECL 1 i可以识别CCR 2 + 在我们最近的人体0/1期PET/CT试验中， 显像CCR 2+细胞与肺纤维化的已知关系以及管理的临床挑战 IPF患者，使这种疾病特别适合于评价放射性示踪剂。因此，我们使用 多个小鼠肺纤维化模型，以显示增加的64 Cu-DOTA-ECL 1 i肺摄取与 CCR 2+细胞浸润和纤维化。我们的数据还表明，放射性示踪剂检测到肺摄取的减少， 阻断白细胞介素-1b（一种在CCR 2+细胞中表达的纤维化介质）后博莱霉素诱导的纤维化， 抗纤维化药物吡非尼酮治疗。IPF患者的初步CCR 2-PET成像显示肺功能增强 信号，特别是在胸膜下纤维化区域。我们建议使用64 Cu-DOTA-ECL 1 i PET成像， 评估在动物模型中纤维化肺病过程中CCR 2+特异性炎症的调节， 验证人类肺组织中CCR 2细胞的检测，并评估监测患者的潜力。我们 假设64 Cu-DOTA-ECL 1 i检测与肺巨噬细胞相关的CCR 2+细胞炎症过程， 纤维化，并可用于监测疾病活动。具体目的是：（1）在小鼠纤维化模型中，评估 在用临床药物治疗后，64 Cu-DOTA-ECL 1 i PET/CT摄取相对于炎症和纤维化的变化 抗纤维化药物和CCR 2拮抗剂的分子靶向治疗，以及（2）在IPF患者中，评估 PET摄取、CT成像与临床状态之间的关系，然后验证PET摄取、CT成像与临床状态之间的关系。 移植后取出的肺中CCR 2介导的炎症和促纤维化基因表达的摄取。 总之，这些目标提供了一个平台，以获得与CCR 2+细胞基础相关的详细信息。 IPF的影像学和可能导致IPF靶向分子治疗的人类研究的解释。

SUMMARY Pulmonary fibrosis is the result of a poorly understood, dysregulated cellular response that is difficult to diagnose and treat. A common form, idiopathic pulmonary fibrosis (IPF), has a progressive, downhill course. There are no well-established molecular biomarkers for diagnosis, treatment, or disease activity. Clinicians currently depend on changes in chest computed tomography (CT) and pulmonary function to monitor patients. Moreover, there are only two approved drug therapies, and treatment is not guided by molecular biomarkers. Lung CCR2+ (C-C motif chemokine receptor 2) inflammatory monocytes and their pathologic progeny, interstitial macrophages, are strongly associated with the experimental development of lung fibrosis, elevated in the lungs of patients with pulmonary fibrosis, and produce profibrotic factors. Fibrosis is significantly attenuated in Ccr2 null mice and by deletion of CCR2+ progeny macrophages, strongly supporting a role for CCR2+ cells in human disease. This proposal aims to utilize a molecular, positron-emission tomography (PET)-based diagnostic to detect CCR2- mediated inflammation in the lungs of patients with fibrosis and to develop targeted therapies. Our multidisciplinary group has established that a peptide-based radiotracer, 64Cu-DOTA-ECL1i, identifies CCR2+ monocytes in animal models and has acceptable dosimetry in our recent human Phase 0/1 trial of PET/CT imaging. The known relationship of CCR2+ cells to pulmonary fibrosis and the clinical challenges of managing patients with IPF, make this disease particularly suited for evaluating the radiotracer. Therefore, we have used multiple mouse models of lung fibrosis to show that increased 64Cu-DOTA-ECL1i lung uptake correlates with CCR2+ cell infiltration and fibrosis. Our data also show that the radiotracer detects decreases in lung uptake in bleomycin-induced fibrosis after blockade of interleukin-1b, a mediator of fibrosis expressed in CCR2+ cells, and treatment with anti-fibrotic drug, pirfenidone. Pilot CCR2-PET imaging of patients with IPF show increased lung signal, particularly in regions of subpleural fibrosis. We propose to use 64Cu-DOTA-ECL1i PET imaging to evaluate modulation of CCR2+-specific inflammation during the course of fibrotic lung disease in animal models, validate the detection of CCR2 cells in human lung tissue, and assess the potential for monitoring patients. We hypothesize that 64Cu-DOTA-ECL1i detects the CCR2+ cell inflammatory process associated with pulmonary fibrosis and can be used to monitor disease activity. Specific aims are: (1) In mouse fibrosis models, assess the change in the 64Cu-DOTA-ECL1i PET/CT uptake relative to inflammation and fibrosis upon treatment with clinical anti-fibrotic drugs and following molecular targeting with CCR2 antagonists, and (2) In patients with IPF, assess the relationship between PET uptake, CT imaging, and clinical status, then validate the relationship of PET uptake with CCR2-mediated inflammation and pro-fibrotic gene expression in lungs removed after transplant. Together, the aims provide a platform to obtain detailed information related to the underpinnings of CCR2+ cell imaging in IPF and the interpretation of human studies that may lead to targeted molecular therapies for IPF.