Geissler Hans J, Dashkevich Alexey, Fischer Uwe M, Fries Jochen W U, Kuhn-Régnier Ferdinand, Addicks Klaus, Mehlhorn Uwe, Bloch Wilhelm
Department of Cardiothoracic Surgery, University of Cologne, Germany.
Eur J Cardiothorac Surg. 2006 May;29(5):767-71. doi: 10.1016/j.ejcts.2005.12.024. Epub 2006 Jan 24.
The lymphatic system plays an important role in interstitial fluid balance, lipid metabolism, and immune response. The recent introduction of specific lymphatic endothelial cell markers has made the investigation of lymphangiogenesis under various conditions and from small tissue samples feasible. It was the purpose of the study to investigate the changes of myocardial lymphatic endothelial markers during the first 12 months after heart transplantation and to analyze if a correlation between lymphatic markers and rejection can be found.
Right ventricular endomyocardial biopsies taken for routine rejection monitoring from 26 heart transplant recipients were investigated. Selected time points were 0.5, 1, 1.5, 6, and 12 months after human heart transplantation (HTX). Immunohistostaining was performed for VEGFR-3, the receptor for lymphangiogenic vascular endothelial growth factors C and D, for LYVE-1, a novel hyaluronan receptor, restricted to lymphatic vessels, and PROX-1, a homeobox gene product, which plays a key role in lymph vessel development and differentiation.
Density of VEGFR-3 positive lymphatics did not change during the first 12 months after transplantation. However, in comparison to the 0.5-month biopsy, density of LYVE-1 and PROX-1 positive lymphatics was significantly decreased at 1 month after transplantation (p<0.03) and at the subsequent time points (p<0.01). Patients with only moderate rejection during the first 12 months (ISHLT<IIIa) had a significantly higher density of VEGFR-3 at 0.5 month in comparison to patients with at least one episode of clinically relevant rejection (ISHLT IIIa or worse, p<0.03).
Myocardial lymphatics show a significant change of endothelial phenotype after transplantation, as demonstrated by significant quantitative changes of lymphatic endothelial marker density. Patients with at least one rejection of ISHLT IIIa or higher had a significantly lower density of VEGFR-3 at 0.5 month after transplantation. The results of this study warrant further investigation on the impact of transplantation on the lymphatic endothelium. The cause-effect relation between rejection and lymphatic endothelium remains to be investigated.
淋巴系统在组织液平衡、脂质代谢和免疫反应中发挥着重要作用。近期特异性淋巴管内皮细胞标志物的引入使得在各种条件下以及从小组织样本中研究淋巴管生成成为可能。本研究旨在调查心脏移植后前12个月内心肌淋巴管内皮标志物的变化，并分析淋巴管标志物与排斥反应之间是否存在相关性。
对26例心脏移植受者用于常规排斥反应监测的右心室心内膜活检组织进行研究。选定的时间点为人心脏移植（HTX）后0.5、1、1.5、6和12个月。对淋巴管生成性血管内皮生长因子C和D的受体VEGFR-3、一种仅限于淋巴管的新型透明质酸受体LYVE-1以及在淋巴管发育和分化中起关键作用的同源盒基因产物PROX-1进行免疫组织化学染色。
移植后前12个月VEGFR-3阳性淋巴管的密度没有变化。然而，与0.5个月时的活检相比，移植后1个月（p<0.03）及随后各时间点（p<0.01）LYVE-1和PROX-1阳性淋巴管的密度显著降低。在最初12个月内仅有中度排斥反应（国际心脏和肺移植学会分级<IIIa级）的患者在0.5个月时VEGFR-3的密度显著高于至少有一次临床相关排斥反应（国际心脏和肺移植学会分级IIIa级或更严重，p<0.03）的患者。
心肌淋巴管在移植后内皮表型出现显著变化，表现为淋巴管内皮标志物密度的显著定量变化。至少有一次国际心脏和肺移植学会分级IIIa级或更高排斥反应的患者在移植后0.5个月时VEGFR-3的密度显著降低。本研究结果值得进一步研究移植对淋巴管内皮细胞产生的影响。排斥反应与淋巴管内皮细胞之间的因果关系仍有待研究。
