The physiology of the lymphatic system.

This paper presents an overview of the anatomy, physiology, and biology of the lymphatic system specifically relevant to lymphatic drug delivery. We will briefly review the classic fluid and solute transport literature, and also examine the current research in lymphatic endothelial cell biology and tumor metastasis in the lymphatics because of the increasing potential for targeted delivery of immunomodulators, chemotherapeutics, and genetic material to specific lymph nodes (Refs. [1-7]).

[1]  J. Burke,et al.  ULTRASTRUCTURAL STUDIES ON THE LYMPHATIC ANCHORING FILAMENTS , 1968, The Journal of cell biology.

[2]  L. Leak STUDIES ON THE PERMEABILITY OF LYMPHATIC CAPILLARIES , 1971, The Journal of cell biology.

[3]  E. Tschachler,et al.  Lymphatic endothelium and Kaposi's sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. , 1998, Cancer research.

[4]  T. Ohhashi,et al.  Active and passive mechanical characteristics of bovine mesenteric lymphatics. , 1980, The American journal of physiology.

[5]  A. Hagiwara,et al.  A new drug-delivery-system of anticancer agents: activated carbon particles adsorbing anticancer agents. , 1987, In vivo.

[6]  M. Johnston Experimental biology of the lymphatic circulation , 1985 .

[7]  A. Taylor,et al.  Interaction of Capillary and Tissue Forces in the Cat Small Intestine , 1976, Circulation research.

[8]  B. Zweifach,et al.  Contractile stimuli in collecting lymph vessels. , 1977, The American journal of physiology.

[9]  Gnepp Dr The bicuspid nature of the valves of the peripheral collecting lymphatic vessels of the dog. , 1976 .

[10]  L. Orci,et al.  In vitro angiogenic and proteolytic properties of bovine lymphatic endothelial cells. , 1994, Experimental cell research.

[11]  A. Hagiwara,et al.  Anticancer agents adsorbed by activated carbon particles, a new form of dosage enhancing efficacy on lymphnodal metastases. , 1986, Anticancer research.

[12]  Shen Yl,et al.  Microlymphaticovenous anastomosis in the treatment of lower limb obstructive lymphedema: analysis of 91 cases. , 1985 .

[13]  G. Schmid-Schönbein,et al.  Microlymphatics and lymph flow. , 1990, Physiological reviews.

[14]  A. Bollinger,et al.  Flow velocity of single lymphatic capillaries in human skin. , 1996, The American journal of physiology.

[15]  K. Alitalo,et al.  Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Engeset,et al.  Lymphatic Pathways from the Tail in Rats and Mice , 1960 .

[17]  Yihai Cao,et al.  Proteolytic processing regulates receptor specificity and activity of VEGF‐C , 1997, The EMBO journal.

[18]  R. Jain,et al.  Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. , 1997, Science.

[19]  N. Pettigrew,et al.  Lymphatic metastasis and its treatment. , 1987, Cancer treatment reviews.

[20]  G. Azzali The ultrastructural basis of lipid transport in the absorbing lymphatic vessel. , 1982, Journal of submicroscopic cytology.

[21]  N P Reddy,et al.  A note on the mechanisms of lymph flow through the terminal lymphatics. , 1975, Microvascular research.

[22]  G. Fábián Investigations into the lymphatic vessels and their valves in the fore-limb of the pig. , 1983, Lymphology.

[23]  L. Liotta,et al.  Tumor invasion and metastasis: an imbalance of positive and negative regulation. , 1991, Cancer research.

[24]  Y. Tan Basic fibroblast growth factor-mediated lymphangiogenesis of lymphatic endothelial cells isolated from dog thoracic ducts: effects of heparin. , 1998, The Japanese journal of physiology.

[25]  J. Weinstein,et al.  Monoclonal antitumor antibodies in the lymphatics. , 1984, Cancer treatment reports.

[26]  A. Jackson Intramuscular absorption and regional lymphatic uptake of liposome-entrapped inulin. , 1981, Drug metabolism and disposition: the biological fate of chemicals.

[27]  P. Gullino,et al.  Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. , 1975, Cancer research.

[28]  P. Mortimer,et al.  The pathophysiology of lymphedema , 1998, Cancer.

[29]  R L Jackson,et al.  Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes. , 1991, Physiological reviews.

[30]  J. R. Casley-Smith Large colloidal osmotic pressures across large pores, and the uptake of macromolecules up their own concentration gradients. , 1981, Microvascular research.

[31]  S. Strand,et al.  Radiolabeled colloids and macromolecules in the lymphatic system. , 1989, Critical reviews in therapeutic drug carrier systems.

[32]  J. Nagy Lymphatic and nonlymphatic pathways of peritoneal absorption in mice: physiology versus pathology. , 1992, Blood purification.

[33]  L. Liotta,et al.  Use of anti‐basement membrane antibodies to distinguish blood vessel capillaries from lymphatic capillaries , 1983, The American journal of surgical pathology.

[34]  G. Schmid-Schönbein,et al.  Lymph pump mechanics in the rabbit hind leg. , 1996, The American journal of physiology.

[35]  M. Johnston,et al.  Pressure-volume relationships in sheep mesenteric lymphatic vessels in situ: response to hypovolemia. , 1998, Microvascular research.

[36]  B. Persson,et al.  Particle sizing and biokinetics of interstitial lymphoscintigraphic agents. , 1983, Seminars in nuclear medicine.

[37]  J. Skandalakis I wish I had been there: highlights in the history of lymphatics. , 1995, The American surgeon.

[38]  L. Leak Interaction of the peritoneal cavity to intraperitoneal stimulation: A peritoneal model system to monitor cellular and extracellular events in the formation of granulation tissue. , 1985, The American journal of anatomy.

[39]  R K Jain,et al.  Transport in lymphatic capillaries. I. Macroscopic measurements using residence time distribution theory. , 1996, The American journal of physiology.

[40]  A. Bollinger,et al.  Fluctuation of skin lymphatic capillary pressure in controls and in patients with primary lymphedema. , 1994, International journal of microcirculation, clinical and experimental.

[41]  H. Patel,et al.  Lymph node localization of non-specific antibody-coated liposomes. , 1985, Life sciences.

[42]  D. Jackson,et al.  LYVE-1, a New Homologue of the CD44 Glycoprotein, Is a Lymph-specific Receptor for Hyaluronan , 1999, The Journal of cell biology.

[43]  D. Moffatt,et al.  Quantitation of changes in lymph protein concentration during lymph node transit. , 1982, The American journal of physiology.

[44]  Steven A. Stacker,et al.  VEGF-D promotes the metastatic spread of tumor cells via the lymphatics , 2001, Nature Medicine.

[45]  F. Hetzel,et al.  Lymphatic diameters and radionuclide clearance in a murine melanoma model. , 1997, Archives of surgery.

[46]  K. Wolff,et al.  Immunoelectron Microscopic Characterization of Human Dermal Lymphatic Microvascular Endothelial Cells: Differential Expression of CD31, CD34, and Type IV Collagen with Lymphatic Endothelial Cells vs Blood Capillary Endothelial Cells in Normal Human Skin, Lymphangioma, and Hemangioma In Situ , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[47]  A. Hargens Tissue fluid pressure and composition , 1982 .

[48]  W. Oldendorf,et al.  Terminal endothelial cells of lymph capillaries as active transport structures involved in the formation of lymph in rat skin. , 1993, Lymphology.

[49]  B. Zweifach,et al.  Micromanipulation of pressure in terminal lymphatics in the mesentery. , 1975, The American journal of physiology.

[50]  E. Rollins,et al.  Intestinal mucosal lymphatic permeability: an electron microscopic study of endothelial vesicles and cell junctions. , 1970, Journal of ultrastructure research.

[51]  J. Mcgeown,et al.  Effects of varying patterns of external compression on lymph flow in the hindlimb of the anaesthetized sheep. , 1988, The Journal of physiology.

[52]  G. Miserocchi,et al.  Proteoglycan involvement during development of lesional pulmonary edema. , 1998, The American journal of physiology.

[53]  W. Comper,et al.  Physiological function of connective tissue polysaccharides. , 1978, Physiological reviews.

[54]  J. R. Casley-Smith Varying total tissue pressures and the concentration of initial lymphatic lymph. , 1983, Microvascular research.

[55]  N. Weidner,et al.  Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  R. Depompolo,et al.  Focused review: postmastectomy lymphedema. , 1996, Archives of physical medicine and rehabilitation.

[57]  L. Yong,et al.  A comparative study of cultured vascular and lymphatic endothelium. , 1991, Experimental pathology.

[58]  Thomas Hawighorst,et al.  Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis , 2001, Nature Medicine.

[59]  P. A. Nicoll,et al.  Behavior of lymphatic vessels in the living rat , 1944 .

[60]  P. Mortimer,et al.  Starling pressures in the human arm and their alteration in postmastectomy oedema. , 1994, The Journal of physiology.

[61]  R K Jain,et al.  Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental validation. , 1999, Journal of biomechanics.

[62]  M. Kanter The lymphatic system: an historical perspective. , 1987, Plastic and reconstructive surgery.

[63]  P. Mortimer Therapy Approaches for Lymphedema , 1997, Angiology.

[64]  M. Shibata,et al.  Mechanism of macromolecule concentration in collecting lymphatics in rat mesentery. , 1997, Microvascular research.

[65]  A. Grodzinsky,et al.  Electromechanical and physicochemical properties of connective tissue. , 1983, Critical reviews in biomedical engineering.

[66]  F. Boccardo,et al.  Derivative lymphatic microsurgery: Indications, techniques, and results , 1995, Microsurgery.

[67]  G. Nicolaysen,et al.  Interstitial fluid volume: local regulatory mechanisms. , 1981, Physiological reviews.

[68]  G. Azzali Ultrastructure of small intestine submucosal and serosal-muscular lymphatic vessels. , 1982, Lymphology.

[69]  V. Ferrans,et al.  Characterization of a Transformed Ovine Lymphatic Endothelial Cell Line , 1999, Microcirculation.

[70]  B. A. Burrows,et al.  Lymphatic flow in human subjects as indicated by the disappearance of 1-131-labeled albumin from the subcutaneous tissue. , 1961, The Journal of clinical investigation.

[71]  L. Leak The transport of exogenous peroxidase across the blood-tissue-lymph interface. , 1972, Journal of ultrastructure research.

[72]  A. Taylor,et al.  Lymph formation and flow. , 1977, Annual review of physiology.

[73]  J. Lauweryns Stereomicroscopic funnel-like architecture of pulmonary lymphatic valves. , 1971, Lymphology.

[74]  L. Leak Electron microscopic observations on lymphatic capillaries and the structural components of the connective tissue-lymph interface. , 1970, Microvascular research.

[75]  V. Torchilin Affinity liposomes in vivo: factors influencing target accumulation , 1996, Journal of molecular recognition : JMR.

[76]  P. D. Watson,et al.  Early kinetics of large molecule transport between plasma and lymph in dogs. , 1980, The American journal of physiology.

[77]  J. Hopewell,et al.  The measurement of skin lymph flow by isotope clearance--reliability, reproducibility, injection dynamics, and the effect of massage. , 1990, The Journal of investigative dermatology.

[78]  L. Leak,et al.  Lymphangiogenesis in vitro: formation of lymphatic capillary-like channels from confluent monolayers of lymphatic endothelial cells. , 1994, In vitro cellular & developmental biology. Animal.

[79]  A. D. Van den Abbeele,et al.  Return of lymphatic function after flap transfer for acute lymphedema. , 1999, Annals of surgery.

[80]  P. D. McMaster,et al.  THE LYMPHATIC PARTICIPATION IN HUMAN CUTANEOUS PHENOMENA : A STUDY OF THE MINUTE LYMPHATICS OF THE LIVING SKIN. , 1933 .

[81]  J. R. Casley-Smith ENDOTHELIAL PERMEABILITY. THE PASSAGE OF PARTICLES INTO AND OUT OF DIAPHRAGMATIC LYMPHATICS. , 1964, Quarterly journal of experimental physiology and cognate medical sciences.

[82]  D. Patton,et al.  Whole-body lymphangioscintigraphy: preferred method for initial assessment of the peripheral lymphatic system. , 1989, Radiology.

[83]  T. Ryan Structure and function of lymphatics. , 1989, The Journal of investigative dermatology.

[84]  K. Alitalo,et al.  VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. , 1999, American Journal of Pathology.

[85]  Judit Darózy Pathology of lymphedema , 1995 .

[86]  R. Baumeister,et al.  Treatment of Lymphedemas by Microsurgical Lymphatic Grafting: What Is Proved? , 1990, Plastic and reconstructive surgery.

[87]  D. Negrini,et al.  Contribution of lymphatic myogenic activity and respiratory movements to pleural lymph flow. , 1994, Journal of applied physiology.

[88]  T. Hardingham,et al.  Proteoglycans: many forms and many functions , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[89]  R. D. Hogan,et al.  The initial lymphatics as sensors of interstitial fluid volume. , 1986, Microvascular research.

[90]  S. Eccles,et al.  Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). , 1996, Cancer research.

[91]  H. Granger,et al.  Characterization of intact mesenteric lymphatic pump and its responsiveness to acute edemagenic stress. , 1989, The American journal of physiology.

[92]  T. Ohhashi,et al.  Effect of potassium on membrane potential and tension development in bovine mesenteric lymphatics. , 1982, Microvascular research.

[93]  D. Neukam,et al.  Ultrastructural studies on the invasion of melanomas in initial lymphatics of human skin. , 1992, The Journal of investigative dermatology.

[94]  J. Casley‐Smith Are the initial lymphatics normally pulled open by the anchoring filaments? , 1980, Lymphology.

[95]  T. Ohhashi,et al.  Electrical Activity of Lymphatic Smooth Muscles , 1977, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[96]  M. Spiegel,et al.  Lymphatic capillary pressure in patients with primary lymphedema. , 1993, Microvascular research.

[97]  C. Porter Drug delivery to the lymphatic system. , 1997, Critical reviews in therapeutic drug carrier systems.

[98]  H. Granger,et al.  Distribution, propagation, and coordination of contractile activity in lymphatics. , 1993, The American journal of physiology.

[99]  H. O. Fadnes Colloid osmotic pressure in interstitial fluid and lymph from rabbit subcutaneous tissue. , 1981, Microvascular research.

[100]  R K Jain,et al.  Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. , 1990, Journal of the National Cancer Institute.

[101]  W. Olszewski,et al.  Flow and composition of leg lymph in normal men during venous stasis, muscular activity and local hyperthermia. , 1977, Acta physiologica Scandinavica.

[102]  L. Liotta,et al.  Cancer invasion and metastasis: positive and negative regulatory elements. , 1991, Cancer investigation.

[103]  V. Stella,et al.  Lymphatic Transport of Drugs , 1992 .

[104]  A. Taylor,et al.  Time course of lymph protein concentration in the dog. , 1977, Microvascular research.

[105]  David A. Berk,et al.  Transport in Lymphatic Capillaries: II. Microscopic Velocity Measurement with Fluorescence Recovery After Photobleaching , 1996 .

[106]  O'Morchoe Pj,et al.  DIFFERENCES IN LYMPHATIC AND BLOOD CAPILLARY PERMEABILIITY ULTRASTRUCTURAL- FUNCTIONAL CORRELATIONS , 1987 .

[107]  J. Levick Flow through interstitium and other fibrous matrices. , 1987, Quarterly journal of experimental physiology.

[108]  H. Bohlen,et al.  Lymphatic pathways and role of valves in lymph propulsion from small intestine. , 1988, The American journal of physiology.

[109]  E. M. Renkin,et al.  Influence of lymph flow rate on concentrations of proteins and dextran in dog leg lymph. , 1973, Lymphology.

[110]  N P Reddy,et al.  Intrinsic propulsive activity of thoracic duct perfused in anesthetized dogs. , 1981, Microvascular research.

[111]  Joseph Schlessinger,et al.  Signal transduction by receptors with tyrosine kinase activity , 1990, Cell.

[112]  Leak Lv The structure of lymphatic capillaries in lymph formation. , 1976 .

[113]  R K Jain,et al.  Barriers to drug delivery in solid tumors. , 1994, Scientific American.

[114]  N. McHale,et al.  The effect of anesthetics on lymphatic contractility. , 1989, Microvascular research.

[115]  V. Richardson,et al.  POTENTIAL APPLICATIONS OF LIPOSOMES TO THERAPY * , 1978, Annals of the New York Academy of Sciences.

[116]  W. Wood,et al.  Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[117]  I. Roddie,et al.  Spontaneous activity in isolated bovine mesenteric lymphatics , 1973, The Journal of physiology.

[118]  M. Hashida,et al.  Fate of lipid and encapsulated drug after intramuscular administration of liposomes prepared by the freeze-thawing method in rats. , 1985, Chemical & pharmaceutical bulletin.

[119]  J. Fendler,et al.  Liposomes as drug carriers. , 1977, Life sciences.

[120]  H. Harcke,et al.  A multiscintigraphic approach to imaging of lymphedema and other causes of the congenitally enlarged extremity. , 1993, Seminars in nuclear medicine.

[121]  R. Gerli,et al.  Morphometric analysis of elastic fibers in human skin lymphatic capillaries. , 1989, Lymphology.

[122]  J. Buckwalter,et al.  Electron microscopic studies of cartilage proteoglycans. Direct evidence for the variable length of the chondroitin sulfate-rich region of proteoglycan subunit core protein. , 1982, The Journal of biological chemistry.

[123]  L. Leak Lymphatic removal of fluids and particles in the mammalian lung. , 1980, Environmental health perspectives.

[124]  J. Kurebayashi,et al.  Expression of Vascular Endothelial Growth Factor (VEGF) Family Members in Breast Cancer , 1999, Japanese journal of cancer research : Gann.

[125]  J. Baert,et al.  Fine filaments in lymphatic endothelial cells , 1976, The Journal of cell biology.

[126]  U. Weidle,et al.  Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination. , 1997, The American journal of pathology.

[127]  G. Schmid-Schönbein Mechanisms causing initial lymphatics to expand and compress to promote lymph flow. , 1990, Archives of histology and cytology.

[128]  R. Reed,et al.  Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. , 1993, Physiological reviews.

[129]  G. Miserocchi,et al.  Involvement of lung interstitial proteoglycans in development of hydraulic- and elastase-induced edema. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[130]  K. Alitalo,et al.  A novel vascular endothelial growth factor, VEGF‐C, is a ligand for the Flt4 (VEGFR‐3) and KDR (VEGFR‐2) receptor tyrosine kinases. , 1996, The EMBO journal.

[131]  J. R. Casley-Smith,et al.  Excess plasma proteins as a cause of chronic inflammation and lymphoedema: Quantitative electron microscopy , 1981, The Journal of pathology.

[132]  R. J. Parsons,et al.  THE EFFECT OF THE PULSE UPON THE FORMATION AND FLOW OF LYMPH , 1938, The Journal of experimental medicine.

[133]  K. Alitalo,et al.  Vascular endothelial growth factor C induces angiogenesis in vivo. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[134]  A. Bollinger Microlymphatics of human skin. , 1993, International journal of microcirculation, clinical and experimental.

[135]  B. W. Zweifach,et al.  Fluid pressures in the rabbit popliteal afferent lymphatics during passive tissue motion. , 1997, Lymphology.

[136]  C. Piacentini,et al.  Scanning and transmission electron microscopy of rabbit heart lymphatic capillaries. , 1991, Lymphology.

[137]  A. Castenholz Morphological characteristics of initial lymphatics in the tongue as shown by scanning electron microscopy. , 1984, Scanning electron microscopy.

[138]  A. Hagiwara,et al.  Cancer chemotherapy administered by activated carbon particles and liposomes. , 1989, Critical reviews in oncology/hematology.

[139]  H. Wiig,et al.  Limits to steady-state lymph flow rates derived from plasma-to-tissue uptake measurements. , 1994, Microvascular research.

[140]  K. Alitalo,et al.  VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. , 1997, Developmental biology.

[141]  J. Burke,et al.  Fine structure of the lymphatic capillary and the adjoining connective tissue area. , 1966, The American journal of anatomy.

[142]  J. Weinstein,et al.  Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence. , 1986, Cancer research.

[143]  N. Staub,et al.  A quantitative radioautographic comparison of albumin concentration in different dized lymph vessels in normal mouse lungs. , 1975, Microvascular research.

[144]  J. Hall,et al.  Intrinsic rhythmic propulsion of lymph in the unanaesthetized sheep. , 1965, The Journal of physiology.

[145]  R. Gerli,et al.  Ultrastructural cytochemistry of anchoring filaments of human lymphatic capillaries and their relation to elastic fibers. , 1991, Lymphology.

[146]  Savage Rc The surgical management of lymphedema. , 1984 .

[147]  L. Gerber,et al.  A review of measures of lymphedema , 1998, Cancer.

[148]  M. Intaglietta,et al.  Effects of anesthesia on the spontaneous activity of the microvasculature. , 1984, International journal of microcirculation, clinical and experimental.

[149]  G. Gregoriadis,et al.  Fate of cholesterol-rich liposomes after subcutaneous injection into rats. , 1983, Biochimica et biophysica acta.

[150]  R. G. Morgan,et al.  Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone. , 1993, The New England journal of medicine.

[151]  B. Zetter,et al.  Adhesion molecules in tumor metastasis. , 1993, Seminars in cancer biology.

[152]  W. Olszewski,et al.  Intrinsic contractility of prenodal lymph vessels and lymph flow in human leg. , 1980, The American journal of physiology.

[153]  K. M. Hwang,et al.  Monoclonal antibodies in the lymphatics: selective delivery to lymph node metastases of a solid tumor. , 1983, Science.

[154]  G. Miserocchi,et al.  Pulmonary interstitial pressure and proteoglycans during development of pulmonary edema. , 1996, The American journal of physiology.

[155]  K. Alitalo,et al.  Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[156]  J. Hay,et al.  Characterization of ovine lymphatic endothelial cells and their interactions with lymphocytes. , 1994, Lymphology.

[157]  R. Jain,et al.  Cells shed from tumours show reduced clonogenicity, resistance to apoptosis, and in vivo tumorigenicity , 1999, British Journal of Cancer.