定量研究猪部分肝移植模型肝窦微循环血流灌注异常在小肝综合征移植肝损伤机制中的作用

Small-for-size syndrome (SFSS) seriously threatened recipient life after living donor liver transplantation. The disturbance of sinusoidal microcirculatory hemodynamic state is the key point for its onset. How to accurately evaluate the sinusoidal microcirculatory perfusion state and its influence on the liver graft are the keys for revealing the mechanisms of SFSS liver injuries. In this study, procine models with different proportions of liver graft will be built for studying the microcirculatory hemodynamic changes with different graft size and the influences on the graft. And the splenic artery will be constricted with varying degree in another group of SFSS procine models with 20% liver graft for studying the hemodynamic changes before and after the procedures and the graft prognosis. Combined with intravital fluorescence microscopy, four-dimensional CT perfusion (4D CTP) technique will be used to quantitatively evaluate hepatic sinusoidal microcirculatory perfusion changes in the process of SFSS, including the influence of hepatic artery and portal vein perfusion changes on hepatic sinusoidal perfusion rate, sinusoidal arterial/portal flow proportion, hepatic sinusoidal resistance and sinusoidal blood flow velocity. Reference to histopathological, immunohistochemical and serological results, the mechanisms of liver injury in SFSS to hepatic sinusoidal structure, mitochondrial function, hepatocyte apoptosis and regeneration will also be analyzed from the microcirculation hemodynamic point of view. In this study, the possibility and feasibility of using 4D CTP indexes for evaluating the graft injury in SFSS and guiding liver blood flow regulation for SFSS treatment will be explored to provide a theoretical basis for early diagnosis and effective control of SFSS. This subject will provide a new approach for studying the occurrence and prognosis of SFSS.

小肝综合征（SFSS）是威胁活体肝移植术后受体生存的重要原因，肝窦微循环血流动力学障碍是其发病的中心环节，如何准确评价肝窦微循环血流灌注状态及其对移植肝的影响是揭示SFSS肝损伤机制的关键。本课题拟建立不同比例猪部分肝移植模型和不同程度脾动脉缩窄治疗的猪SFSS模型，应用4D CT全肝灌注技术结合活体荧光显微镜检测，定量分析SFSS发生发展过程中肝动脉、门静脉血流灌注变化对移植肝微循环肝窦灌注率/灌注量、肝窦内肝动脉/门静脉血流组成比例、肝窦阻力及血流速度的影响，并与反映肝窦结构、肝细胞线粒体功能、肝细胞凋亡和再生的血清学、免疫组化及病理组织学指标对照，从微循环水平揭示SFSS的肝损伤机制，探索以4D CTP血流灌注指标评估肝损伤情况及指导SFSS移植肝血流调节治疗的可行性，从而为早期诊断和有效防治SFSS提供理论依据。本课题为从微循环血流动力学角度研究SFSS发病机制及转归提供了新思路。

小肝综合征（SFSS）是威胁活体肝移植术后受体生存的重要原因，肝窦微循环血流动力学障碍是其发病的中心环节，如何准确评价肝脏微循环血流灌注状态及其对移植肝的影响是揭示SFSS肝损伤机制的关键。为避免排斥反应、血管并发症等因素对肝脏微循环血流状态的影响，保证手术稳定性和研究进度，我们采用部分肝切除术建立SFSS大鼠模型，并以脾切除方法治疗SFSS；应用4D CT全肝灌注技术，定量分析SFSS发生发展过程中肝动脉、门静脉血流灌注变化对移植肝微循环肝动脉、门静脉血流灌注的影响，并与反映肝窦结构、肝细胞凋亡和再生的血清学、免疫组化及病理组织学指标对照，从微循环水平揭示SFSS的肝损伤机制，探索以4D CTP血流灌注指标评估肝损伤情况及指导SFSS血流调节治疗的可行性，从而为早期诊断和有效防治SFSS提供理论依据。此外，本课题还应用 IVIM-DWI、T2map、T2*技术无创性、定量监测部分肝切除术后残肝的各项参数变化，与病理组织学结合，分析了上述各项MR指标与形态学损伤的相关性，发现应用T2map技术获得的组织T2值与残肝窦状隙改变、肝细胞水肿及空泡样变均有显著相关性，用其诊断肝脏损伤具有较高的敏感性和特异性；ADCstd和ADCslow也有较高的诊断特异性；从而客观分析了上述技术应用于移植肝损伤评价的可能性。目前在此领域，国内外尚无相关研究报道，属于本研究重要创新，有可能进一步缩小肝脏穿刺活检等有创性诊断方法的应用范围，进而造福患者。综上所述，本项目研究结果对指导临床医生进一步推进LDLT技术开展和保护供、受体安全都具有直接的现实意义；也进一步提高了影像学检查在肝移植围手术期评估中的应用价值和应用范围。