Pulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis. Rats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls. The bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31. SPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.

中文翻译：

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使用血管内皮示踪剂对博莱霉素引起的肺纤维化中的肺血管疾病进行 SPECT 成像

合并特发性肺纤维化 (IPF) 的肺动脉高压 (PH) 与较差的结果相关。非常需要一种非侵入性诊断方式来检测和评估肺血管疾病 (PVD) 的严重程度。99mTc-PulmoBind 是一种新型显像剂，可与肺微血管内皮上的肾上腺髓质素 (AM) 受体结合。使用内皮细胞示踪剂 99mTc-PulmoBind 的 SPECT 成像用于评估与肺纤维化相关的 PVD。将患有选择性右肺博来霉素诱导的纤维化的大鼠与对照大鼠进行比较。三周后使用 99mTc-PulmoBind 和 99mTc-白蛋白大聚集体 (MAA) 进行 SPECT 成像。通过超声心动图评估 PH 和右心室 (RV) 功能。通过荧光微血管造影评估肺灌注。通过 qPCR 和免疫组织学测量肺 AM 受体表达。通过测量来自 IPF 患者和健康对照的肺活检中 AM 受体的表达来探索与人类 IPF 的相关性。用荧光微血管造影术评估，博来霉素组出现优先的右肺纤维化，伴有重塑和灌注减少。这些大鼠出现 PH 并伴有 RV 肥大和功能障碍。右肺中 99mTc-PulmoBind 的摄取选择性降低了 50%，并且与 AM 受体表达降低、PH 和 RV 肥大有关。AM受体与肺泡毛细血管内皮细胞蛋白CD31共表达，博来霉素后显着降低。与 99mTc-MAA 相比，99mTc-PulmoBind 摄取的定量动态分析表明，后者仅根据流量分布，左肺摄取增加约 60%，而 99mTc-PulmoBind 的左肺摄取不受影响。来自人类 IPF 患者的肺显示与 CD31 密切相关的 AM 受体表达显着降低。使用 99mTc-PulmoBind 进行 SPECT 成像可检测 PVD ​​及其在博莱霉素诱导的肺纤维化中的严重程度。人类 IPF 中 AM 受体表达的降低支持这种成像方法的进一步临床开发。