Qi Jinwei, Chen Junlin, von Stillfried Saskia, Kozcera Patrick, Shi Yang, Rix Anne, Kiessling Fabian
From the Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany (J.Q., J.C., P.K., Y.S., A.R., F.K.); and Institute of Pathology, Medical Faculty, RWTH Aachen University, Aachen, Germany (S.V.).
Invest Radiol. 2025 Jun 1;60(6):407-413. doi: 10.1097/RLI.0000000000001143. Epub 2024 Nov 29.
Inflammatory bowel disease (IBD) subdivides into Crohn disease (CD) and ulcerative colitis (UC), and is characterized by unpredictable periods of inflammation and results in significant patient suffering and even death. Conventional diagnostic methods, for example, colonoscopy, computed tomography, or magnetic resonance imaging, have limitations such as invasiveness, patient discomfort, and limited sensitivity and accuracy. Therefore, we propose ultrasound molecular imaging (USMI) to detect and characterize IBD. First, we evaluated integrin-α v β 3 as a biomarker of IBD in human samples and then used clinically translatable cyclic Arg-Gly-Asp-D-Phe-Lys (cRGDfK)-coupled poly(butyl)cyanoacrylate microbubbles (cRGD-MB) to assess IBD in mice.
Vascular integrin-α v β 3 expression in human colon tissue samples (healthy, CD and UC, n = 10 per group) was analyzed by immunofluorescence staining. In mice, acute colitis was induced by administration of 4% dextran sodium sulfate in drinking water for 5 days. On day 7, USMI with cRGD-MB was performed in colitis (n = 6) and healthy (n = 5) mice. The signal of bound cRGD-MB was assessed by the destruction-replenishment method. Ex vivo analysis of mouse colon tissue was performed to assess the degree of colitis by hematoxylin-eosin staining and the vascular expression of integrin-α v by immunofluorescence.
Human samples showed a significantly higher vascular integrin-α v β 3 expression in CD and UC tissue, when compared with healthy samples ( P < 0.005). In mice, a higher binding of cRGD-MB to inflamed colon was detected by USMI compared with healthy controls ( P < 0.005). Immunofluorescence staining confirmed these findings, showing stronger integrin-α v expression in acute colitis, with a good correlation between USMI signal intensity and integrin-α v expression ( r = 0.8, P = 0.0016).
Integrin-α v β 3 on vessels is a suitable marker for IBD. USMI using cRGD-MB accurately detects this marker and correlates well with histology. These encouraging results support clinical translation of this imaging method as a noninvasive and cost-effective monitoring tool.
炎症性肠病（IBD）分为克罗恩病（CD）和溃疡性结肠炎（UC），其特征为炎症发作期不可预测，给患者带来巨大痛苦甚至导致死亡。传统诊断方法，如结肠镜检查、计算机断层扫描或磁共振成像，存在诸如侵入性、患者不适以及敏感性和准确性有限等局限性。因此，我们提出采用超声分子成像（USMI）来检测和表征IBD。首先，我们在人体样本中评估整合素αvβ3作为IBD的生物标志物，然后使用可临床转化的环化精氨酸 - 甘氨酸 - 天冬氨酸 - D - 苯丙氨酸 - 赖氨酸（cRGDfK）偶联的聚（丁基）氰基丙烯酸酯微泡（cRGD - MB）来评估小鼠的IBD。
通过免疫荧光染色分析人类结肠组织样本（健康、CD和UC，每组n = 10）中的血管整合素αvβ3表达。在小鼠中，通过在饮用水中给予4%葡聚糖硫酸钠5天诱导急性结肠炎。在第7天，对结肠炎小鼠（n = 6）和健康小鼠（n = 5）进行cRGD - MB超声分子成像。通过破坏 - 补充法评估结合的cRGD - MB的信号。对小鼠结肠组织进行离体分析，通过苏木精 - 伊红染色评估结肠炎程度，并通过免疫荧光评估整合素αv的血管表达。
与健康样本相比，人体样本显示CD和UC组织中的血管整合素αvβ3表达显著更高（P < 0.005）。在小鼠中，与健康对照相比，超声分子成像检测到cRGD - MB与发炎结肠的结合更高（P < 0.005）。免疫荧光染色证实了这些发现，显示急性结肠炎中整合素αv表达更强，超声分子成像信号强度与整合素αv表达之间具有良好的相关性（r = 0.8，P = 0.0016）。
血管上的整合素αvβ3是IBD的合适标志物。使用cRGD - MB的超声分子成像准确检测到该标志物，并且与组织学相关性良好。这些令人鼓舞的结果支持将这种成像方法临床转化为一种无创且经济高效的监测工具。
