cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis
cis-4-[18F]fluoro-L-proline Molecular Imaging Experimental Liver Fibrosis
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DOI：
10.3389/fmolb.2020.00090
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发表时间：
2020-05-15
影响因子：
5
通讯作者：
Dilsizian, Vasken
中科院分区：
文献类型：
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作者：
Cao, Qi;Lu, Xin;Dilsizian, Vasken
简介：早期肝纤维化可能是可逆的，但难以诊断。临床管理将加强发展的非侵入性成像技术，能够识别肝损伤早期，终末期纤维化enescope。使用靶向肝星状细胞（HSC）中胶原生成的氨基酸脯氨酸类似物顺式-4-[F-18]氟-L-脯氨酸（[F-18]氟-脯氨酸）检测纤维化。方法：采用无水乙醇喂养8周，沿着灌胃暴饮暴食，同时注射脂多糖（LPS），建立急性脂肪性肝炎动物模型。对照动物接受对照饲料8周，并按照与急性脂肪性肝炎模型相同的时间表接受等体积的盐水。首先，在体外细胞实验进行评估[H-3]脯氨酸摄取的HSC，肝细胞和枯否细胞来自急性脂肪性肝炎大鼠（n= 14）和对照组（n= 14）。接下来，进行离体肝脏实验以研究急性脂肪性肝炎（n= 5）和对照（n= 5）中未标记的脯氨酸介导的胶原合成及其相关的脯氨酸转运蛋白表达。最后，在急性脂肪性肝炎动物模型（n = 7）和对照小鼠（n = 7）中进行体内动态和静态[F-18]氟脯氨酸micro-PET/CT成像。结果：脂肪性肝炎大鼠HSC孵育60 min后，[H-3]脯氨酸摄取量是对照组的5倍，[H-3]脯氨酸摄取量与肝胶原表达之间存在良好的相关性（r值> 0.90，p < 0.05）。随后的肝组织研究表明，急性脂肪性肝炎动物中脯氨酸转运蛋白的表达比对照组高2-3倍，这种转运蛋白抑制剂阻断了脯氨酸相关的胶原蛋白合成。在[F-18]氟脯氨酸的体内micro-PET/CT研究中，急性脂肪性肝炎小鼠肝脏的摄取比对照组高2-3倍。在急性脂肪性肝炎小鼠肝脏中[F-18]氟脯氨酸摄取与肝脏胶原表达之间存在良好的相关性（r值= 0.97，p < 0.001）。结论：[F-18]氟脯氨酸位于肝脏中，与急性脂肪性肝炎的胶原生成相关，其信号强度足够高，可以使用微型PET/CT进行成像。因此，[F-18]氟脯氨酸可作为PET成像生物标志物用于检测早期肝纤维化。
Introduction:Early-stage liver fibrosis is potentially reversible, but difficult to diagnose. Clinical management would be enhanced by the development of a non-invasive imaging technique able to identify hepatic injury early, before end-stage fibrosis ensues. The analog of the amino acid proline,cis-4-[F-18]fluoro-L-proline ([F-18]fluoro-proline), which targets collagenogenesis in hepatic stellate cells (HSC), was used to detect fibrosis. Methods:Acute steatohepatitis was induced in experimental animals by liquid ethanol diet for 8 weeks, intra-gastric binge feedings every 10th day along with lipopolysaccharide (LPS) injection. The control animals received control diet for 8 weeks and an equivalent volume of saline on the same schedule as the acute steatohepatitis model. First,in vitrocellular experiments were carried out to assess [H-3]proline uptake by HSC, hepatocytes and Kupffer cells derived from rats with acute steatohepatitis (n= 14) and controls (n= 14). Next,ex vivoliver experiments were done to investigate unlabeled proline-mediated collagen synthesis and its associated proline transporter expression in acute steatohepatitis (n= 5) and controls (n= 5). Last,in vivodynamic and static [F-18]fluoro-proline micro-PET/CT imaging was performed in animal models of acute steatohepatitis (n = 7) and control (n = 7) mice. Results:[H-3]proline uptake was 5-fold higher in the HSCs of steatohepatitis rats than controls after incubation of up to 60 min. There was an excellent correlation between [H-3]proline uptake and liver collagen expression (r-value > 0.90,p< 0.05). Subsequent liver tissue studies demonstrated 2-3-fold higher proline transporter expression in acute steatohepatitis animals than in controls, and proline-related collagen synthesis was blocked by this transporter inhibitor.In vivomicro-PET/CT studies with [F-18]fluoro-proline showed 2-3-fold higher uptake in the livers of acute steatohepatitis mice than in controls. There was an excellent correlation between [F-18]fluoro-proline uptake and liver collagen expression in the livers of acute steatohepatitis mice (r-value = 0.97,p< 0.001). Conclusion:[F-18]fluoro-proline localizes in the liver and correlates with collagenogenesis in acute steatohepatitis with a signal intensity that is sufficiently high to allow imaging with micro-PET/CT. Thus, [F-18]fluoro-proline could serve as a PET imaging biomarker for detecting early-stage liver fibrosis.