Preclinical SPECT/CT Imaging of αvβ6 Integrins for Molecular Stratification of Idiopathic Pulmonary Fibrosis
Preclinical SPECT/CT Imaging of αvβ6 Integrins for Molecular Stratification of Idiopathic Pulmonary Fibrosis
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DOI：
10.2967/jnumed.113.120592
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发表时间：
2013-12-01
影响因子：
9.3
通讯作者：
Marshall, John F.
中科院分区：
文献类型：
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作者：
John, Alison E.;Luckett, Jeni C.;Marshall, John F.
由α v β 6整合素激活的转化生长因子是特发性肺纤维化发病机制的核心。α v β 6整合素在纤维化肺组织中的表达增加，是治疗该疾病的一个有希望的治疗靶点。目前，测量肺中α v β 6整合素水平需要对活检样本进行免疫组织化学分析。这种方法在临床上对许多肺纤维化患者是不切实际的，因此迫切需要一种无创策略来测量肺中α v β 6整合素水平，以促进疾病进展和治疗反应的监测。方法：采用博莱霉素诱导的小鼠肺损伤模型，通过纳米spect /CT成像评估静脉注射in- 111标记的α v β 6特异性（二乙烯三胺五乙酸四酯[DTPA]-A20FMDV2）或对照（DTPA- a20fmdvran）肽的结合。肺羟脯氨酸含量测定纤维化程度，肺α v β 6蛋白和itgb6信使RNA测定纤维化程度。结果：静脉给药1小时后，肺内检测到in -111标记的A20FMDV2肽与α v β 6整合素的最大结合。注射对照肽的小鼠未检测到明显的结合。与生理盐水暴露的小鼠相比，博来霉素暴露的小鼠肺部整合素结合增加，并通过α v β 6阻断抗体预处理减弱。in -111标记的A20FMDV2肽水平与羟脯氨酸、α v β 6蛋白和itgb6信使RNA水平呈正相关。结论：我们开发了一种高度敏感、可量化、无创的技术来测量肺内α v β 6整合素水平。通过SPECT/CT扫描测量α v β 6整合素有可能用于肺纤维化患者的分层治疗。
Transforming growth factor beta activation by the alpha v beta 6 integrin is central to the pathogenesis of idiopathic pulmonary fibrosis. Expression of the alpha v beta 6 integrin is increased in fibrotic lung tissue and is a promising therapeutic target for treatment of the disease. Currently, measurement of alpha v beta 6 integrin levels in the lung requires immunohistochemical analysis of biopsy samples. This procedure is clinically impractical for many patients with pulmonary fibrosis, and a noninvasive strategy for measuring alpha v beta 6 integrin levels in the lungs is urgently required to facilitate monitoring of disease progression and therapeutic responses. Methods: Using a murine model of bleomycin-induced lung injury, we assessed the binding of intravenously administered In-111-labeled alpha v beta 6-specific (diethylenetriamine pentaacetate-tetra [DTPA]-A20FMDV2) or control (DTPA-A20FMDVran) peptide by nanoSPECT/CT imaging. Development of fibrosis was assessed by lung hydroxyproline content, and alpha v beta 6 protein and itgb6 messenger RNA were measured in the lungs. Results: Maximal binding of In-111-labeled A20FMDV2 peptide to alpha v beta 6 integrins was detected in the lungs 1 h after intravenous administration. No significant binding was detected in mice injected with control peptide. Integrin binding was increased in the lungs of bleomycin-, compared with saline-, exposed mice and was attenuated by pretreatment with alpha v beta 6-blocking antibodies. Levels of In-111-labeled A20FMDV2 peptide correlated positively with hydroxyproline, alpha v beta 6 protein, and itgb6 messenger RNA levels. Conclusion: We have developed a highly sensitive, quantifiable, and noninvasive technique for measuring alpha v beta 6 integrin levels within the lung. Measurement of alpha v beta 6 integrins by SPECT/CT scanning has the potential for use in stratifying therapy for patients with pulmonary fibrosis.