T1mapping技术下肝细胞靶向对比剂早期诊断化疗后肝损伤的机制研究

Chemotherapy induced liver injuries (CASH and SOS) in patients with colorectal liver metastasis increases incidence of postoperative complications and reduce the long-term survival rate, so there is important clinical value on early diagnosis. However, there is no effective way on early diagnosis of CASH and SOS. Our previous study found that when the liver cells damaged, the liver cell membrane transporters organic transit peptide (OATP) and the multi-drug resistance protein (MRP) levels would change. Gadoxetic acid, liver cell targeted contrast agent, in liver cell metabollism was affected and this change could be quantitative maker by T1 mapping with T1 relaxation time. Therefore, we hypothesize that using Gadoxeetic acid-enhanced MRI can diagnose and differentiate between CASH and SOS early, at the same time for moitoring the liver reserve function. However, the mechanism of the research is still rarely understood. This topic will explore the relationship between the values of T1 relaxation time with the pathological grade on CASH and SOS by means of molecular imaging and molecular biology research, and with the expressions of OATP and MRP and the liver cell damage factor (IL-6, TNF-α) at the same time. Also, we hope to find the law of the relationship between the index reflecting the liver reserve function of the blood test（ALT、AST、T-BIL、ALB）with expressions of OATP and MRP. Finally, we can provide an accurate imaging basis for the individualized comprehensive treatment plan for colorectal cancer patients with liver metastases.

结直肠癌肝转移患者的化疗相关性肝损伤（CASH和SOS）增加患者术后并发症的发生并降低中远期存活率，因此早期诊断有重要临床价值。但目前尚无早期诊断CASH和SOS的有效方法。我们前期研究结果发现肝细胞破坏会导致肝细胞膜表面OATP和MRP受体表达的改变，从而影响肝细胞靶向对比剂Gadoxetic acid的细胞内代谢，而这种代谢变化可通过T1mapping的纵向驰豫时间定量标记。因此，我们推测应用该对比剂可早期诊断及鉴别CASH和SOS，并同时用于肝脏储备功能监测。本课题拟运用分子影像学和分子生物学手段研究：纵向驰豫时间值与CASH和SOS不同病理分级、肝细胞OATP和MRP分子水平及肝细胞损伤因子（IL-6、TNF-α）的相关性；探索肝脏储备功能的血液指标（ALT、AST、T-BIL、ALB）与 OATP、MRP间关系的规律，从而为结直肠癌肝转移患者制定个体化精准治疗方案。

结直肠癌化疗相关性肝损伤分为非酒精性脂肪性肝病和肝窦损伤，制约多学科综合治疗方案制定、化疗效果及再次手术干预。本研究拟通过“T1mapping的T1弛豫时间”客观显示化疗相关性肝损伤吸收Gadoxetic acid对比剂的差异性，从而早期、准确及定量反映化疗相关性肝损伤的不同分级的病理改变及相应的肝脏储备功能。主要研究内容为：①完成了Gadoxetic acid增强磁共振检查对于C57BL/6小鼠检查参数的设置并完成对照组10只C57BL/6小鼠的扫描。肝胆特异期T1弛豫值平均值为398.4±43.4（milliseconds），OATP1平均灰度值为29952.1±11475。②化疗相关性脂肪性肝病C57BL/6小鼠的模型建立。实验组根据不同的给药时间，分为2、4、6周组，各10只小鼠，每周2次腹腔注射奥沙利铂6mg／kg。测量计算肝胆特异期T1弛豫时间值及首过快速上升期中的增强斜率百分比（first rapid enhancement slope percentage，ESP）（％）。肝胆特异期T1弛豫时间值在正常组和肝纤维化组及不伴有肝纤维化的肝细胞变性组和肝纤维化组之间都具有统计学差异。ESP在正常组、不伴有肝纤维化的肝细胞变性组及肝纤维化组间皆具有明显统计学差异。肝胆特异期T1弛豫时间值和ESP可有效评估化疗相关性肝损伤的不同分级的病理改变。③野百合碱诱导C57BL/6小鼠肝窦阻塞综合征模型建立。实验组共11只C57BL/6小鼠行增强磁共振检查5天前，腹腔注射野百合碱360mg/kg。增强后T1弛豫时间值在正常组（n=10）和SOS组分别为408.87±27.21和150.75±21.73，两者之间具有明显统计学差异；ESP正常组和SOS组分别为4.14±0.96和10.10±4.97，两者具有明显统计学差异；OATP1平均灰度值正常组和SOS组分别为29952.1±11475和422060±178634，两者具有明显统计学差异。肝胆特异期T1弛豫时间值和ESP可有效评估肝窦损伤。主要的科学价值在于：通过T1mapping的T1弛豫时间客观显示化疗相关性肝损伤吸收对比剂的差异性，与肝细胞膜表面OATP1水平的相关性，从而揭示Gadoxetic acid的成像机制，为结直肠癌肝转移的个体化综合治疗提供更为精准的影像辅助检查技术。