Die Atrophie/Hypertrophie-Antwort nach Pfortaderastligatur beeinflusst durch zeitversetzte Freisetzung von Wachstumsfaktoren hepatische Umbauvorgänge und induziert mikrovaskuläres Remodelling, Hyperoxygenierung und Zellproliferation in der ligierten Leber

Abstract

Portal branch ligation (PBL) is increasingly used prior to hepatectomy for colorectal metastases to enable curative liver resection. Clinical studies indicate that tumors within the ligated lobe develop accelerated growth. Therefore, the aim of our study was to evaluate in a mouse model how far PBL influences hepatic artery response, liver microcirculation, tissue oxygenation and cell proliferation within the ligated and non-ligated liver. Therefore, we used intravital multifluorescence microscopy, laser Doppler fluxmetry, immunohistochemistry and biochemical techniques to examine microcirculatory responses, microvascular remodeling and cellular consequences after left lateral PBL in BALB/c mice. During the first 7d PBL significantly increased cell proliferation within the non-ligated liver leading to hypertrophy accompanied by EGF and VEGF expression. Within the ligated lobe PBL induced a reduction of left hilar blood flow by ~ 50 %. This resulted in 80 % sinusoidal perfusion failure, significant parenchymal hypoxia and liver atrophy. After 14 d, however, left hilar blood flow was found restored. Remodeling of the microvasculature included a rarefaction of the sinusoidal network, however, without substantial perfusion failure, compensated by a hepatic arterial buffer response and significant sinusoidal dilatation. This resulted in hyperoxygenation of the tissue, indicating arterialization of the ligated lobe, and significant hepatocellular proliferation as well as weight gain of the ligated lobe. This late microvascular remodeling was associated with increased HO-1, VEGF and eNOS expression. These findings may explain the accelerated tumor progression occasionally observed in patients after PBL.