Risk and recovery of outflow obstruction in living-related liver transplantation: The influence of liver perfusion on regeneration and outcome

灌注相关的问题是肝移植术后许多并发症的原因。流出道梗阻是成人活体肝脏捐献的关键外科问题之一，因为供体肝脏必须分成两个半肝，并且必须切断肝中静脉分支。引流不充分会损害肝功能并导致依赖区域的再生受损，从而通过功能性肝脏质量的额外减少增加患者的风险。在扩大肝切除的大鼠模型中，通过应用血管导向的实质保留切除技术而不是以前使用的团块结扎技术，实验性地防止了功能性肝质量减少和再生受损。在一个新开发的手术模型中，观察到通过扩张的血窦血管化结合重塑的肝脏结构和受损的再生来恢复流出阻塞区域的受损引流。这些和其他临床和实验观察导致的假设，即局灶性流出道阻塞是关键事件损害的功能能力和再生的依赖领土，这表明局部调节肝再生。这个跨学科项目的第一个目的是评估流出道梗阻在肝功能，再生和血运重建方面的功能相关性，采用大鼠和土拨鼠模型。第二个目的是研究其潜在的机制和药理学调节。第三个目的是评估流出道梗阻不仅在肝切除模型中而且在部分肝移植后的生物学重要性。基于连续的组织切片，将开发用于形态数据的自动分析和三维可视化的软件算法。这将导致更深入地了解局灶性受损的肝脏灌注的调节影响，不仅在体积和血管再生方面对肝再生，而且在肝再生过程中的分子过程的空间分布方面。

Perfusion-related problems account for numerous complications after liver transplantation. Outflow obstruction represents one of the key surgical problems in adult living-related liver donation, as the donor liver has to be split into two hemi-livers and middle hepatic vein branches have to be transected. Insufficient drainage compromising liver function and leading to an impaired regeneration of the dependent territories is the consequence, increasing the risk for the patient by additional reduction of functional liver mass. Reduction of functional liver mass and impaired regeneration were prevented experimentally in rat model of extended liver resection by applying a vessel-oriented parenchyma preserving resection technique instead of the formerly used mass ligation technique. Recovery of the impaired drainage of outflow obstructed areas by vascularization of dilated sinusoids in combination with a remodeled liver architecture and an impaired regeneration was observed in a newly developed surgical model. These and other clinical and experimental observations lead to the hypothesis that focal outflow obstruction is the key event compromising the functional capacity and the regeneration of the dependent territories, suggesting a local regulation of liver regeneration. The first aim of this interdisciplinary project is the evaluation of the functional relevance of outflow obstruction in terms of liver function, regeneration, and revascularization employing the rat and woodchuck model. The second aim is to investigate the underlying mechanism and its pharmacological modulation. The third aim is to assess the biological importance of outflow obstruction not only in the model of liver resection but also after partial liver transplantation. Based on serial histological sections, software algorithms for automatic analysis and three-dimensional visualization of morphological data will be developed. This will lead to a deeper understanding of the regulatory influence of focally impaired liver perfusion not only on liver regeneration in terms of volume and vascular regeneration, but also in terms of the spatial distribution of molecular processes during the course of liver regeneration.