THE LYMPHATICSYSTEMCOMPONENTS, FUNCTIONSAND DISEASES

THE LYMPHATICSYSTEMCOMPONENTS, FUNCTIONSAND DISEASESCONTENTS Preface viiChapter 1 Cerebrospinal Fluid Circulation: Brain Lymphatics, Brain Glymphatics, or Both? Carlo Bellini, Luca A. Ramenghi, Dario Paladini, Tommaso Bellini and Francesco Boccardo 1Chapter 2 Versatility and Innovations of the Greater Omental Flap in the Surgical Treatment of Lymphedema of the Upper and Lower Limbs 15J. M. Lasso, J. Rosado and R. Perez Cano Chapter 3 Molecular Mechanisms of Tumor Lymphangiogenesis Masahiro Tawada, Kazuhiro Yoshida and Shigeru Nakashima 39Chapter 4 New Roles of Lymphangiogenesis in Cancer SpreadPedro Villarejo Campos, David Padilla Valverde and Javier Redondo 63Bibliography 77Index 123 PREFACEThis book provides research on the components, functions anddiseasesofthe lymphatic system. Chapter One reviews the role of lymphatic drainageofcerebrospinal fluid from the brain. In particular, the authors reviewthecurrenthypotheses on the possible drainage of lymphatic fluid fromthe brain. ChapterTwo expose the actual refinements of the surgical technique for thepedicledand free greater omentum flap, facing the treatment lymphedema. ChapterThree summarizes the recent development of the molecular mechanismsoftumor lymphangiogenesis, especially the role of bone marrow-derivedcellsand the growth factors implicated in this process. Chapter Four reviewsmolecular mechanisms related to the activation of tumor lymphangiogenesisand their clinical implications. In: The Lymphatic System ISBN: 978-1-63484-689-9Editor: Christy Ramirez © 2016 Nova Science Publishers, Inc. Chapter 1 CEREBROSPINAL FLUIDCIRCULATION:BRAIN LYMPHATICS, BRAIN GLYMPHATICS, ORBOTH?Carlo Bellini1, , Luca A. Ramenghi1 , DarioPaladini2,Tommaso Bellini1 and Francesco Boccardo3 1Neonatal Intensive Care Unit, Department of Intensive Care, IRCCS Giannina Gaslini Institute, Genoa, Italy 2Fetal Medicine and Surgery Unit, Department of Intensive Care, IRCCS Giannina Gaslini Institute, Genoa, Italy 3Department of Surgery, Unit of Lymphatic Surgery and Microsurgery, San Martino Hospital, University of Genoa, Italy ABSTRACT We briefly review the role of lymphatic drainage of cerebrospinal fluid from the brain. In particular, we review the current hypotheses onthe possible drainage of lymphatic fluid from the brain. The intriguingpoint is that although lymphatics are absent in the brain, a very complexbrain-wide paravascular pathway for cerebrospinal fluid and interstitial fluid exchange is present which allows efficient clearance of solutes and Correspondence to: Carlo Bellini, MD, PhD, Neonatal Intensive Care Unit, Department ofIntensive Care, IRCCS University Hospital Giannina Gaslini Institute, Largo G. Gaslini, 5, 16147 Genoa, Italy, tel. . 2 Carlo Bellini, Luca A. Ramenghi, Dario Paladini et al. waste from the brain. The role of cervical lymphatic vessels is critical andvarious models describing the anatomical connection betweenthesubarachnoid space and the nasal lymphatic vessels are discussed. Keywords: brain lymphatic system, brain glymphatic system, cervical lymphatic vessels BASIC CONCEPTS Extra-cellular fluid is generated through filtration in most tissues.Filtration occurs when the hydrostatic pressure in the capillary exceedstheopposing force represented by the intra-vascular colloid osmotic pressureofthe plasma proteins. The resulting interstitial fluid (ISF), whichcontainsproteins, solutes, and waste substances from the metabolismof thevarioustissues, is drained through the lymphatic system and eventually returns intotheblood. Hence, the role of the lymphatic network, which is ubiquitous inthehuman body, is to filter the cellular waste out of circulating fluids throughoutthe organism. In this scenario, the brain represents an amazing exception, sinceit is completely devoid of lymphatics. This is very unusual, consideringthatthe brain is certainly an energy hog and can falter as soon as its metabolismgives the slightest sign of unbalance. Although scientists have believed for years that cerebrospinal fluid(CSF)acts as the brain’s highly refined lymphatic system, two statementsaretraditionally very difficult to link: as reported above, there are nolymphaticvessels in the brain parenchyma and there is a highly specialized systemthatallows the CSF to move into the brain, thus replacing fluid inside the brain. Anold study by Schwalbe (1869) [1] which involved injecting BerlinBluedyeinto the subarachnoid space in dogs demonstrated that the lymphatic systemisthe main clearing outlet for CSF. This hypothesis was reviewed anddiscussedrepeatedly after its publication. The role of the lymphatic systeminthedrainage of proteins in case of hemorrhage or infection has been reviewedaswell [2, 3]. It has been known since 1872 [4] that there is indeed a circulatoryexit pathway of CSF through the arachnoid granulations into lymphaticvesselsin the nasal mucosa, the frontal sinus and along cranial nerves. Several articlessupport this hypothesis describing experiments performed in different species[5]. This lymph draining pathway, which runs through the olfactorytracts,passes across the cribriform plate (lamina cribrosa) and the nasal mucosaandreaches the retropharyngeal lymph-nodes and, eventually, the nodes at thebase Cerebrospinal Fluid Circulation 3of the neck, was found to be present also in the human body [5]. However,lymphatic drainage may alternatively – or rather, in addition - occur alsothrough nerve pathways other than the cribiform plate, such as theoptic,auditory, trigeminal, or facial nerves, as well as through other cranial andlumbar spinal nerves [5]. The extracellular fluid compartment of the brain is usually dividedintotwo components, i.e., CSF and parenchymal ISF [6]. The most widelyaccepted theory is that CSF is mainly secreted by the four choroidplexuses(CPs) within the brain ventricles, then it flows inside the ventricular cavitiesand reaches the subarachnoid spaces (through the Luschka andMagendieforamina), after which it is mainly conveyed into venous sinuses throughthearachnoid villi (Pacchioni granules). As for the parenchymal ISF, thisisthought to be actively secreted by the capillary endothelial cells; it thenmovesto the capillary glial complex through the perivascular and subependymalregions into the ventricular system and subarachnoid space, where it mixeswith the CSF [7]. This hypothetical model has been widely discussed and criticizedonthebasis of results obtained from “in vivo” studies, leading to the belief that thereis little evidence to continue supporting it [5]. Cerebral spinal fluid is mainly produced by the choroid plexuses whichare made up of infoldings of blood vessels covered by a thin tissue calledpiaand are located in the four ventricles of the brain – the largest of whicharefound in the lateral ventricles. The CSF flows or communicates betweenthelateral ventricles and the third ventricle through the interventricular foramen(also called the foramen of Monro). The cerebral spinal fluid thenslowlyflows from the third ventricle to the fourth ventricle through the aqueduct ofSylvius. From the fourth ventricle, the CSF then passes through the foramenofLuschka and the foramen of Magendie, after which it enters the subarachnoidspace that externally bathes the cerebral structures of the brain and spinal cord.Flowing along the subarachnoid cisterns, the CSF is then reabsorbedbythearachnoid granulations (also called the granulations of Pacchioni) that aremainly distributed along the superior sagittal sinus. In this chapter we would like to briefly review what is nowknownaboutthis fascinating field and to show experimental evidence that CSFruns intothebrain as scientists have indeed, long believed, but that an incrediblyadvancednetwork of anatomical structures, a kind of non-conventional “brainhyperlymphatic highway system,” allows CSF circulation and brain cellular wastefiltering. Finally, in the framework of this still ill-defined mechanism, wewilladdress the fascinating conundrum represented by the human fetus. 4 Carlo Bellini, Luca A. Ramenghi, Dario Paladini et al. CSF PRODUCTION The concepts of CSF production and reabsorption are shown inFigure1.Although there is general agreement that CSF is produced mainly byCPs, twodifferent mechanisms are claimed to be in place for its production. Inthefirst,passive plasma filtration driven by hydrostatic pressure is thought tooccurthrough the fenestrated choroidal capillary endotheliumwith the CSFflowingfrom the basolateral surface towards the apical surface [8]. Thesecondhypothesis states that there is active secretion through the apical surfaceofthechoroidal epithelium, with a very limited, if non-existent, role playedbyhydrostatic or oncotic pressures [9]. The ventricular ependyma has alsorarelybeen reported as a possible additional source of CSF production[5].Considering the existence of a transmantle pressure gradient, i.e., thedifference between the pressure inside