CMKLR1-Targeted Molecular Imaging of Inflammation as a Precision Medicine Tool in Acute Lung Injury and Fibrotic Lung Diseases

摘要 损伤后异常的免疫反应是细胞外基质不良重塑的主要致病因素 急性肺损伤(ALI)和多种肺纤维化疾病(简称炎症-纤维化轴)。 然而，目前还没有确定的方法对调节失调的肺进行无创评估。 发炎。这一差距以及临床病程的病理生理学异质性和变异性。 患者阻碍了对纤维化肺部疾病的精确医学管理。趋化素样受体-1 趋化因子受体(CMKLR1)是一种趋化因子受体，在促纤维化的单核细胞来源的巨噬细胞中过度表达。 白细胞亚群在肺纤维化发病机制中起关键作用。我们的中心目标是确定 CMKLR1靶向PET在I)肺炎症定量成像；II)预测 疾病进展的风险；和iii)早期监测对抗炎和抗炎的反应 实验性ALI和纤维化肺损伤模型中的纤维化干预。我们还将解决临床上的 通过确定CMKLR1靶向PET的表达及其在未来临床翻译中的潜力 新冠肺炎和几种肺纤维化疾病患者肺组织中CMKLR1mRNA的表达 控制。我们的初步数据显示，一种新型的CMKLR1靶向示踪剂在肺中的摄取显著增加 (64Cu-NODAGA-CG34)在脂多糖性ALI和博莱霉素性肝纤维化两种模型中的作用 肺损伤，主要是由单核细胞来源的巨噬细胞积聚所致。我们的中央 假设1)CMKLR1是ALI和ALI中单核细胞来源的巨噬细胞的生物标志物 纤维性肺疾病；因此，其64Cu-NODAGA-CG34 PET的靶向成像允许II)预测 进展为持续性炎症和纤维化的风险；以及iii)监测早期治疗 对抗炎和抗纤维化干预的反应。我们提出三个具体目标： 特异性目的1：检测A)小鼠ALI模型中表达CMKLR1的白细胞的免疫学特性 B)新冠肺炎和纤维化肺疾病患者的肺标本。 具体目标2：验证CMKLR1靶向PET作为不同类型炎症的生物标志物的准确性。 小鼠ALI和纤维化损伤的分期。 具体目标3：确定CMKLR1靶向PET在A)疾病预测中的潜力；以及B)早期 检测小鼠ALI和纤维化肺损伤模型的治疗反应。 影响：通过确定CMKLR1靶向PET在成像巨噬细胞驱动的炎症和 定义CMKLR1在各种纤维化肺疾病中的表达，这一提议可能导致精确 医学战略，允许i)改进风险分层；ii)前瞻性地识别高危患者 对抗炎/抗纤维化干预措施做出良好反应的可能性(因此，避免其他患者 不良影响和费用)；和iii)基于对反应的早期监测的个性化治疗调整。

ABSTRACT Aberrant immune response to injury is a major pathogenic driver of adverse extracellular matrix remodeling after acute lung injury (ALI) and a wide range of fibrotic lung diseases (referred to inflammation-fibrosis axis). However, there is currently no established approach for noninvasive assessment of dysregulated lung inflammation. This gap along with the pathophysiological heterogeneity and variability of the clinical course of patients has hampered precision medicine management of fibrotic lung diseases. Chemokine-like receptor-1 (CMKLR1) is chemokine receptor which is overexpressed in profibrotic monocyte-derived macrophages, a leukocyte subset with crucial roles in the pathogenesis of lung fibrosis. Our central goal is to determine the potential of CMKLR1-targeted PET for i) quantitative imaging of lung inflammation; ii) prognostication of the risk of disease progression; and iii) early monitoring of the response to anti-inflammatory and anti- fibrotic interventions in experimental models of ALI and fibrotic lung injury. We will also address the clinical relevance of CMKLR1-targeted PET and its potential for future clinical translation by determining the expression of CMKLR1 in the lungs of patients with COVID-19 and several categories of fibrotic lung diseases vs. healthy controls. Our preliminary data revealed a significant increase in lung uptake of a novel CMKLR1-targeted tracer (64Cu-NODAGA-CG34) in two murine models of lipopolysaccharide-induced ALI and bleomycin-induced fibrotic lung injury, which was primarily driven by the accumulation of monocyte-derived macrophages. Our central hypothesis is that i) CMKLR1 serves as a biomarker of monocyte-derived macrophages in ALI and fibrotic lung diseases; hence its targeted imaging by 64Cu-NODAGA-CG34 PET allows for ii) predicting the risk of progression into sustained inflammation and fibrosis; and iii) monitoring the early therapeutic response to anti-inflammatory and anti-fibrotic interventions. We propose three Specific Aims: Specific Aim 1: To determine the immunoprofile of CMKLR1-expressing leukocytes in A) murine models of ALI and fibrotic injury, and B) lung specimens of patients with COVID-19 and fibrotic lung diseases. Specific Aim 2: To validate the accuracy of CMKLR1-targeted PET as a biomarker of inflammation at different stages of ALI and fibrotic injury in murine models. Specific Aim 3: To determine the potential of CMKLR1-targeted PET in A) disease prognostication; and B) early detection of the therapeutic response in murine models of ALI and fibrotic lung injury. Impact: By determining the role of CMKLR1-targeted PET for imaging macrophage-driven inflammation and defining the expression of CMKLR1 across various fibrotic lung diseases, this proposal may lead to a precision medicine strategy that allows for i) improved risk stratification; ii) prospective identification of patients with a high likelihood of favorable response to anti-inflammatory/anti-fibrotic interventions (hence, sparing the others from adverse effects and costs); & iii) personalized treatment adjustment based on early monitoring of the response.