Grüntzig Johannes, Hollmann Frank
Klinik für Augenheilkunde, Universitätsklinikum Düsseldorf, Heinrich Heine Universität Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Klinik für Augenheilkunde, Universitätsklinikum Düsseldorf, Heinrich Heine Universität Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Ann Anat. 2019 Jan;221:1-16. doi: 10.1016/j.aanat.2018.08.004. Epub 2018 Sep 18.
Due to its accessible position and tissue heterogeneity, the eye is ideally suited for studying the lymphatic system. As early as the 19th century, questions about the origin and function of this system were discussed. For example, whether Schlemm's canal, which is of particular importance in the pathogenesis of glaucoma, is a lymphatic vessel, or does this vascular system begin with finger-shaped protuberances? Despite the discovery of lymphatic endothelial molecules and the use of molecular imaging technologies, these questions are still discussed controversially today. Leber demonstrated in 1873 with a solution consisting of two dyes of different particle size that only the smaller particles from the anterior chamber of the eye filled the episcleral and conjunctival veins around the corneal margin. He believed to have proven - to be read in the historical review of our article - that the Canalis Schlemmii in humans is a venous circular vessel and not a lymphatic vessel. In our own investigations, we reduced the rather contradictory and complex question of whether there are lymphatic vessels in the eye to the question of whether there are drainage connections between the different sections of the eye and the lymphatic system or not. With different radioactive tracers and combined with unilateral ligation of cervical lymph vessels, we observed outflow from the subconjunctival and retrobulbar space, from the anterior chamber and the vitreous body. The rate of discharge of the radioactive tracer was determined by the radiopharmaceutical and injection site. In analogy to the lymphatic drainage of the head we found a segmental drainage of lymphatic substances on the eye. Vitreous humour and retrobulbar space were drained by lymphatic vessels, predominantly to the deep cervical lymph nodes, while anterior chamber and subconjunctival space drains predominated over the superficial cervical lymph nodes. Eyeball tattoos - as loved by some fan communities - should therefore cause a coloured staining of the superficial cervical lymph nodes. The boundary of the drained segments would be in the area of the eyeball's equator. According to the textbooks, the lymph is actively removed from finger-shaped initial segments via pre-collectors and collectors with properly functioning intraluminal valves and smooth muscle cells in the vessels' media. In patients with spontaneous conjunctival bleeding, however, we observed phenomena in the conjunctival lymph vessels, which ca not be explained with old familiar ideas. At nozzle-shaped vessel constrictions separation of blood components occurred. The erythrocytes formed partially a so-called fluidic "resting bulk layer". Parallel vessel parts caused a retrograde filling of already emptied segments. These observations led our experimental investigations. In the literature, there are different scanning electron microscopy (SEM) images of lymphatic endothelial surfaces; nevertheless they are unassigned to a particular vessel segment. In the conjunctiva, we studied the question whether there is a dependence between vessel diameter and the surface characteristics of endothelial cells (after unfolding by lymphography). A constantly applied photo-mathematical procedure for all specimens allowed determining the size of the cross sections. The specimens were randomized into seven groups with diameters of 0.1-1.0mm and above and examined by SEM. In the smallest vessels (diameter=0.11mm), the impressions of the occasionally occurring nuclei in the lumen were clearly impressive. With increasing diameter, these impressions were lost and the individual endothelial nuclei could no longer be identified. Rather, one recognized only wall-like structures. In vessels of intermediate diameter (0.3-0.4mm), structures could be seen on the surface similar to reticular fibres. With increasing diameters, their prominent character weakened. In the group with diameters above 0.5mm, wavy surface structures were shown. Finally, in vessels of diameters over 1.0mm, a uniform, flat surface was observed. Regardless of the collection site of the specimens, we found certain surface characteristics related to the vessels' calibre. In further investigations by means of interstitial dye lymphography, we were able to demonstrate in the conjunctiva that under increasing injection pressure, additional vessels stained from finger-shaped processes. At least in the conjunctiva, the existence of so-called "blind-ending initial segments" seems doubtful (despite the fact that initial segments or "initial lymphatics" would begin in periphery, not end). Rather, these are likely to be temporary filling states. SEM investigations were carried out on the internal structure of these dome-shaped vessel parts by means of a specially developed preparation technique. Despite numerous variants in the lymphographic design of the blind bags - in the form of finger, balloon, dome, piston, pyramidal, double-humped and spearhead-like endings - slot-shaped, lip-shaped and saw blade-like structures were repeatedly found, similar to a zipper. These findings suggest preformed connections to the next segment and may control lymphatic flow. To clarify the retrograde fluid movements, we examined the lymph vessels' valves or those structures that were previously interpreted as valves. The different structures found could be subdivided into three groups. The lack of common bicuspid structures provides an explanation for retrograde fluid movement. That nevertheless a directional flow is possible, is explained by the flow model developed by Gerhart Liebau. Conjunctival lymphatics show intraluminal structures by double contrast injection, which we divided into four groups due to anatomical differences: An accurate statement about the occurrence of certain intraluminal vascular structures in certain vascular calibres was possible only conditionally. However, complex and extended structures (group d) were found almost exclusively in larger vessel calibres (diameter>0.9mm). The structures are reminiscent of published findings in the "collector channel orifices of Schlemm's canal". They should play an important role in the regulation of the intraocular pressure, or the balance between production and outflow of the aqueous humour. The influence of such structures on the function of the lymphatic vessels is not yet known. As an approach models could be used, which for instance are applied in the water industry for the drainage, the degradation of introduced substances, or the detention pond. The latter serves for the retention and purification of drainage water (storage, treatment and reuse of drainage water). Dead zones, barriers, short-circuit currents and swirling are further hydraulic terms. Can intraluminal vascular structures, for example, affect the lymphatic flow and thus the mechano-sensitivity of lymphatic endothelial cells? Whatever interpretation model we use, the warning of the Swiss anatomist His from 1862 is still true today that all theories about the formation and movement of lymph should be based on precise anatomical basics. This review article therefore tries to make a contribution therefore. Despite knowing of lymphatic endothelial molecules, despite the discovery of the role of lymphangiogenic growth factors in diseases and the use of molecular imaging technologies, we still know too little about the anatomy and function of the lymphatic system.
由于其易于观察的位置和组织异质性,眼睛非常适合用于研究淋巴系统。早在19世纪,关于该系统的起源和功能的问题就已被讨论。例如,在青光眼发病机制中具有特别重要意义的施莱姆管是否是淋巴管,或者这个血管系统是否始于指状突起?尽管发现了淋巴管内皮分子并使用了分子成像技术,但这些问题至今仍存在争议。1873年,莱伯用一种由两种不同粒径染料组成的溶液证明,只有来自眼前房的较小颗粒填充了角膜边缘周围的巩膜上静脉和结膜静脉。他认为自己已经证明——从我们文章的历史回顾中可以读到——人类的施莱姆管是一个静脉环形血管,而不是淋巴管。在我们自己的研究中,我们将眼睛中是否存在淋巴管这个相当矛盾和复杂的问题简化为眼睛不同部分与淋巴系统之间是否存在引流连接的问题。通过使用不同的放射性示踪剂,并结合单侧结扎颈淋巴管,我们观察到了来自结膜下和球后间隙、前房和玻璃体的流出。放射性示踪剂的排出速率取决于放射性药物和注射部位。与头部的淋巴引流类似,我们发现眼睛上存在淋巴物质的节段性引流。玻璃体和球后间隙由淋巴管引流,主要引流至颈深淋巴结,而前房和结膜下间隙的引流则主要引流至颈浅淋巴结。因此,一些粉丝群体喜爱的眼球纹身应该会导致颈浅淋巴结出现彩色染色。引流节段的边界将在眼球赤道区域。根据教科书,淋巴通过具有正常功能的腔内瓣膜和血管中膜平滑肌细胞的前收集器和收集器从指状起始段被主动清除。然而,在自发性结膜出血的患者中,我们在结膜淋巴管中观察到了一些现象,这些现象无法用熟悉的旧观念来解释。在喷嘴状血管狭窄处,血液成分发生分离。红细胞部分形成了所谓的流体“静止主体层”。平行的血管部分导致已经排空的节段逆行充盈。这些观察结果引发了我们的实验研究。在文献中,有不同的淋巴管内皮表面扫描电子显微镜(SEM)图像;然而,它们未被指定到特定的血管节段。在结膜中,我们研究了血管直径与内皮细胞表面特征(通过淋巴造影展开后)之间是否存在相关性的问题。对所有标本持续应用光数学程序可以确定横截面的大小。标本被随机分为七组,直径分别为0.1 - 1.0毫米及以上,并通过SEM进行检查。在最小的血管(直径 = 0.11毫米)中,管腔内偶尔出现的细胞核的印记清晰可见。随着直径增加,这些印记消失,单个内皮细胞核无法再被识别。相反,只能识别出类似壁状的结构。在中等直径(0.3 - 0.4毫米)的血管中,可以看到表面上类似于网状纤维的结构。随着直径增加,它们的突出特征减弱。在直径大于0.5毫米的组中,显示出波浪状表面结构。最后,在直径超过1.0毫米的血管中,观察到均匀、平坦的表面。无论标本的采集部位如何,我们都发现了与血管口径相关的某些表面特征。在通过间质染料淋巴造影进行的进一步研究中,我们能够在结膜中证明,在注射压力增加的情况下,从指状突起处有额外的血管被染色。至少在结膜中,所谓“盲端起始段”的存在似乎值得怀疑(尽管起始段或“初始淋巴管”会始于周边,而非末端)。相反,这些可能是暂时的充盈状态。通过一种专门开发的制备技术,对这些穹顶状血管部分的内部结构进行了SEM研究。尽管盲袋的淋巴造影设计有多种变体——呈手指、气球、穹顶、活塞、金字塔、双峰和矛头状末端等形式——但反复发现了类似拉链的槽状、唇状和锯片状结构。这些发现表明与下一个节段有预先形成的连接,并且可能控制淋巴流动。为了阐明逆行液体运动,我们检查了淋巴管瓣膜或那些以前被解释为瓣膜的结构。发现的不同结构可分为三组。缺乏常见的双尖瓣结构为逆行液体运动提供了解释。然而,仍有可能实现定向流动,这由格哈特·利鲍提出的流动模型来解释。通过双重造影注射,结膜淋巴管显示出腔内结构,由于解剖学差异,我们将其分为四组:只有在一定条件下才能准确说明某些腔内血管结构在特定血管口径中的出现情况。然而,复杂且延伸的结构(d组)几乎只在较大血管口径(直径 > 0.9毫米)中发现。这些结构让人联想到在“施莱姆管的收集通道口”中已发表的发现。它们应该在眼内压的调节或房水生成与流出的平衡中发挥重要作用。这种结构对淋巴管功能的影响尚不清楚。作为一种方法,可以使用例如在水工业中用于排水、引入物质降解或滞洪池的模型。后者用于滞留和净化排水(排水的储存、处理和再利用)。死区、屏障、短路电流和漩涡是进一步的水力学术语。例如,腔内血管结构会影响淋巴流动,进而影响淋巴管内皮细胞的机械敏感性吗?无论我们使用何种解释模型,瑞士解剖学家希斯在1862年提出的警告如今仍然适用,即所有关于淋巴形成和运动的理论都应基于精确的解剖学基础。因此,这篇综述文章试图为此做出贡献。尽管我们知道淋巴管内皮分子,尽管发现了淋巴管生成生长因子在疾病中的作用并使用了分子成像技术,但我们对淋巴系统的解剖学和功能仍然知之甚少。