Division of Radiological Sciences and Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Mol Imaging Biol. 2021 Dec;23(6):905-913. doi: 10.1007/s11307-021-01617-w. Epub 2021 Jun 16.
We tested whether the translocator protein (TSPO)-targeted positron emission tomography (PET) tracer, N-acetyl-N-(2-[C]methoxybenzyl)-2-phenoxy-5-pyridinamine ([C]PBR28), could distinguish macrophage dominant from neutrophilic inflammation better than 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) in mouse models of lung inflammation and assessed TSPO association with macrophages in lung tissue from the mouse models and in patients with chronic obstructive pulmonary disease (COPD).
MicroPET imaging quantified [C]PBR28 and [F]FDG lung uptake in wild-type (Wt) C57BL/6J or heterozygous transgenic monocyte-deficient Wt/opT mice at 49 days after Sendai virus (SeV) infection, during macrophage-dominant inflammation, and in Wt mice at 3 days after SeV infection or 24 h after endotoxin instillation during neutrophilic inflammation. Immunohistochemical staining for TSPO in macrophages and neutrophils was performed using Mac3 and Ly6G for cell identification in mouse lung sections and CD68 and neutrophil elastase (NE) in human lung sections taken from explanted lungs from patients with COPD undergoing lung transplantation and donor lungs rejected for transplantation. Differences in tracer uptake among SeV-infected, endotoxin-treated, and uninfected/untreated control mice and in TSPO staining between neutrophils and macrophage populations in human lung sections were tested using analysis of variance.
In Wt mice, [C]PBR28 uptake (% injected dose/ml lung tissue) increased significantly with macrophage-dominant inflammation at 49 days (D49) after SeV infection compared to controls (p = <0.001) but not at 3 days (D49) after SeV infection (p = 0.167). [C]PBR28 uptake was unchanged at 24 h after endotoxin instillation (p = 0.958). [F]FDG uptake increased to a similar degree in D3 and D49 SeV-infected and endotoxin-treated Wt mice compared to controls with no significant difference in the degree of increase among the tested conditions. [C]PBR28 but not [F]FDG lung uptake at D49 post-SeV infection was attenuated in Wt/opT mice compared to Wt mice. TSPO localized predominantly to macrophages in mouse lung tissue by immunostaining, and TSPO staining intensity was significantly higher in CD68+ cells compared to neutrophils in the human lung sections.
PET imaging with [C]PBR28 can specifically detect macrophages versus neutrophils during lung inflammation and may be a useful biomarker of macrophage accumulation in lung disease.
我们测试了 TSPO 靶向正电子发射断层扫描 (PET) 示踪剂 N-乙酰基-N-(2-[C]甲氧基苄基)-2-苯氧基-5-吡啶胺 ([C]PBR28) 是否比 2-脱氧-2-[F]氟-D-葡萄糖 ([F]FDG) 更能区分肺部炎症中的巨噬细胞优势与中性粒细胞炎症，并评估 TSPO 与肺部炎症小鼠模型和慢性阻塞性肺疾病 (COPD) 患者肺组织中的巨噬细胞之间的关联。
MicroPET 成像定量了野生型 (Wt) C57BL/6J 或杂合转单核细胞缺陷 Wt/opT 小鼠在感染仙台病毒 (SeV) 49 天后、巨噬细胞优势炎症期间以及在感染 SeV 3 天后或内毒素灌注后 24 小时的 [C]PBR28 和 [F]FDG 肺部摄取。使用 Mac3 和 Ly6G 对小鼠肺组织切片中的巨噬细胞和中性粒细胞进行 TSPO 免疫组织化学染色，并用 CD68 和中性粒细胞弹性蛋白酶 (NE) 对从 COPD 患者接受肺移植和供体肺因移植而被拒绝的肺移植中取出的人肺组织切片进行染色。分析方差用于测试 SeV 感染、内毒素处理和未感染/未处理对照小鼠之间示踪剂摄取的差异，以及人肺组织切片中中性粒细胞和巨噬细胞群体之间 TSPO 染色的差异。
在 Wt 小鼠中，与对照组相比，感染 SeV 49 天后 (D49) 的 [C]PBR28 摄取量 (%注射剂量/ml 肺组织) 显著增加( p <0.001)，但感染 SeV 3 天后 (D49) 则没有增加 ( p = 0.167)。内毒素灌注后 24 小时 [C]PBR28 摄取量无变化 ( p = 0.958)。与对照组相比，D3 和 D49 SeV 感染和内毒素处理的 Wt 小鼠的 [F]FDG 摄取量增加到相似程度，在测试条件之间，增加程度没有显著差异。与 Wt 小鼠相比，感染 SeV 后 D49 的 [C]PBR28 肺部摄取在 Wt/opT 小鼠中被减弱。通过免疫染色，[C]PBR28 在小鼠肺组织中主要定位于巨噬细胞，并且与人类肺组织切片中的中性粒细胞相比，CD68+细胞中的 TSPO 染色强度显著更高。
用 [C]PBR28 进行正电子发射断层扫描成像可以特异性地检测肺部炎症中的巨噬细胞与中性粒细胞，并且可能是肺部疾病中巨噬细胞积累的有用生物标志物。
