The physiology of the lymphatic system

https://doi.org/10.1016/S0169-409X(01)00150-8Get rights and content

Abstract

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], [2], [3], [4], [5], [6], [7]).

Introduction

Physicians have observed components of what is now known as the lymphatic system since ancient times (for historical reviews, see Refs. [11], [12], [13], [14]). Hippocrates described ‘white blood in nodes’ in one of history’s earliest known medical texts, On the Glands. Likewise, Aristotle noted fibers containing colorless fluid located between blood vessels and nerves. Much later, various aspects of lymph, lymphatic drainage, and lymphatic anatomy enjoyed significant attention in the 17th and 18th centuries. The lymphatic system was first recognized by Gasparo Aselli as early as 1627, the same century the vascular circulation was described by William Harvey. Classic studies by Swammerdam in the mid-1600s first revealed valves in the collecting lymphatic vessels using wax injections, and Louis Petit demonstrated the spread of breast cancer to axillary lymph nodes in the early 1700s. Indeed, the anatomy of the lymphatic system was almost completely characterized by the early 19th century. However, while knowledge of the blood circulation continued to grow rapidly in the last century, our understanding of the lymphatic system progressed at an exceedingly slower rate. For example, although Budge [15] and Sala [16] had described the developing lymphatic system of chick embryos at the end of the 19th century, it is still controversial whether lymphatic vessels sprout from veins, form de novo from lymphangioblasts, or both [17]. Furthermore, despite observations for centuries of lymphatic dissemination of many cancers, the mechanisms of lymphatic metastasis are still unclear today.

The lymphatics comprise a one-way transport system for fluid and proteins by collecting them from the interstitial space and returning them to the blood circulation. The simplified relation between blood, interstitium, and lymph is depicted in Fig. 1. As blood travels from the branching arteries down to the smallest capillaries, plasma fluid and proteins are forced out into the interstitial space. Most of this exudate gets reabsorbed into the post-capillary venules, but because of osmotic forces resulting from protein extravasation, there is a small net fluid flux out of the vasculature. This excess fluid is convected through the interstitium and into the initial lymphatics, which are freely permeable to macromolecules and thus serve a primary role in maintaining osmotic and hydrostatic pressures within the tissue space. The net fluid efflux, and therefore the net flow rate of lymph, is approximately 100–500 times less than the flow rate of the blood.

Because of the high permeability of the initial lymphatics, there is little, if any, exclusion of interstitial molecules. The protein composition of lymph is nearly equivalent to that of interstitial fluid, which in turn is similar to, but usually less concentrated than, that of blood plasma. The exception to this is intestinal lymph, which contains a high amount of fat resorbed directly from the intestine. This lymph is a turbid, milky emulsion and is often referred to as ‘chyle’.

The extracellular matrix (ECM) plays an integral role in lymphatic function, and will be discussed in Section 3.1. Fluid equilibrium is tightly controlled by the cooperation of both components, and an offset in either lymphatic function or the mechanical integrity of the ECM can result in fluid accumulation, edema, and/or fibrosis. Such an imbalance is becoming more and more common as secondary effects of radiation therapy and surgical procedures such as mastectomy [18] (for a brief discussion on edema, see Section 8).

In addition to regulating tissue fluid balance, the lymphatics serve as a major transport route for immune cells and disseminating tumor cells along with interstitial macromolecules. While traveling in the lymphatic system, cells and particles experience lower flow rates and smaller shear stresses than they would in the blood circulation. Furthermore, the lymph nodes act as holding reservoirs; it is here where white blood cells proliferate and disseminating tumor cells take root and form metastatic tumors. For all these reasons, the lymphatic route provides several targeting advantages over the blood circulation for drug delivery. In particular, there is great potential for concentrating immunomodulators, chemotherapeutics, and imaging agents to specified lymph nodes, avoiding dose-limiting systemic side effects, systemic dilution, and liver degradation.

Section snippets

Organization of the lymphatic system

There are five main categories of conduits in the lymphatic system: the capillaries, collecting vessels, lymph nodes, trunks, and ducts. Their sizes range from 10 μm to 2 mm in diameter. Lymph forms when interstitial fluid moves into the lymphatic capillaries. It then drains from the capillaries into the collecting vessels, which pass through at least one but usually several clusters of lymph nodes. Collecting vessels both enter and exit the nodes, where lymph has access to the blood via the

Mechanisms of lymph formation and transport

Two components contribute to the net flow rate in the lymphatics: lymph formation and lymph propulsion. The first describes fluid transport from the interstitium into the initial lymphatics, while the second refers to the systemic forces which drive lymph from the initial capillaries into the collecting vessels, through the nodes and ducts, and eventually back to the blood. These two components are coupled. If there is blockage in the systemic route (e.g., removal of a lymph node), interstitial

Solute uptake

The interpretation of lymphatic uptake data requires careful consideration of (a) the pre-lymphatic path of the solute molecule and (b) the location and conditions of sampling. Although the endothelial cell junctions of the initial lymphatics are not tight and considered freely permeable to most proteins, the physicochemical properties of the ECM can affect interstitial solute transport. Since the solute must travel at least some distance through the interstitium before entering the lymphatics,

Methods for assessing lymphatic function

Lymphatic function is often characterized by a tissue clearance rate, which describes the removal of injected, radiolabeled molecules or particles in terms of amount per unit time per unit tissue volume. This method is straightforward and provides a semi-quantitative measure of lymphatic function [33], [126]. Lymph formation can be observed in skin and mesentery by injecting an optical contrast agent such as mercury [127], [128], [129], [130] or, as demonstrated in Fig. 5, fluorescently labeled

Biology of the lymphatic system

There are many biological similarities between the endothelium of blood vessels and that of lymphatics. For example, the requirements and characteristics of cell growth are similar [140] and lymphocyte binding to lymphatic endothelial cells is not significantly different from binding to venous or arterial endothelial cells [141]. With respect to morphogenetic properties, lymphatic endothelial cells (LECs) behave similarly to vascular endothelial cells (VECs) in vitro. They both exhibit

Tumors and lymphatic metastasis

The lymphatics serve as a primary route for the dissemination of many solid tumors, particularly those of epithelial origin including breast, colon, lung, and prostate. Tumor metastasis is a complex process and it is difficult to demonstrate commonalities among different types of cancers. Some cancers metastasize solely through the blood, some through the lymphatics, and some use both routes at various stages in their development. Despite its importance, little is understood about

Edema

Edema is a condition of tissue fluid imbalance often resulting from infection, trauma (from burns or radiation), surgery, and tissue grafting and transplantation [179], [180], [181]. It can also be congenital. Although edema affects millions of people, treatment options are scarce and discouraging. Attempts at treatment have included drug therapy, physical therapy, and surgical approaches, but these have shown limited success [182], [183], [184], [185], [186], [187].

The pathological basis of

Conclusion

This paper has attempted to briefly outline the physiology of the lymphatic system, particularly pertaining to solute transport. Special attention was given to recent advances in lymphatic endothelial cell biology, tumor metastasis, and lymphedema, since these are quickly gaining importance in lymphatic drug delivery issues (particularly the role of lymphangiogenesis in tumor metastasis) and are typically not addressed in reviews on lymphatic physiology. Throughout this review, the intrinsic

References (190)

  • N.P. Reddy et al.

    A note on the mechanisms of lymph flow through the terminal lymphatics

    Microvasc. Res.

    (1975)
  • N.G. McHale et al.

    The effect of anesthetics on lymphatic contractility

    Microvasc. Res.

    (1989)
  • T. Ohhashi et al.

    Effect of potassium on membrane potential and tension development in bovine mesenteric lymphatics

    Microvasc. Res.

    (1982)
  • C.J. Porter

    Drug delivery to the lymphatic system

    Crit. Rev. Ther. Drug Carrier Syst.

    (1997)
  • M.A. Steller et al.

    Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence

    Cancer Res.

    (1986)
  • J.N. Weinstein et al.

    Monoclonal antitumor antibodies in the lymphatics

    Cancer Treat. Rep.

    (1984)
  • J.N. Weinstein et al.

    Monoclonal antibodies in the lymphatics: selective delivery to lymph node metastases of a solid tumor

    Science

    (1983)
  • J.A. Nagy

    Lymphatic and nonlymphatic pathways of peritoneal absorption in mice: physiology versus pathology

    Blood Purif.

    (1992)
  • G.W. Schmid-Schönbein

    Microlymphatics and lymph flow

    Physiol. Rev.

    (1990)
  • D.R. Gnepp

    Vascular endothelial markers of the human thoracic duct and lacteal

    Lymphology

    (1987)
  • J.E. Skandalakis

    I wish I had been there: highlights in the history of lymphatics

    Am. Surgeon

    (1995)
  • M.A. Kanter

    The lymphatic system — an historical perspective

    Plastic Reconstr. Surg.

    (1987)
  • F. Tischendorf

    The lymphatic system and its history

    Biochem. Exp. Biol.

    (1978)
  • S.E. Leeds

    Three centuries of history of the lymphatic system

    Surg. Gynecol. Obstet.

    (1977)
  • A. Budge, Über lymphherzen bei hühnerembryonen, Arch. Anat. Entwickl.-Gesch. (1880)...
  • L. Sala

    Sullo sviluppo dei cuori linfatici e dei dotti torici nell’ embryone di pollo

    Ric. Lab. Anat. Norm. Univ. Roma

    (1900)
  • J. Wilting et al.

    Embryonic lymphangiogenesis

    Cell Tissue Res.

    (1999)
  • M.J. Brennan et al.

    Focused review: postmastectomy lymphedema

    Arch. Phys. Med. Rehabil.

    (1996)
  • L.V. Leak

    The structure of lymphatic capillaries in lymph formation

    Fed. Proc.

    (1976)
  • R.D. Hogan et al.

    Mechanical control of initial lymphatic contractile behavior in bat’s wing

    Am. J. Physiol.

    (1986)
  • L.V. Leak et al.

    Ultrastructural studies on the lymphatic anchoring filaments

    J. Cell Biol.

    (1968)
  • L.V. Leak et al.

    Fine structure of the lymphatic capillary and the adjoining connective tissue area

    Am. J. Anat.

    (1966)
  • K. Aukland et al.

    Interstitial-lymphatic mechanisms in the control of extracellular fluid volume

    Physiol. Rev.

    (1993)
  • T.H. Adair et al.

    Lymph formation and its modification in the lymphatic system

  • T.H. Adair et al.

    Quantitation of changes in lymph protein concentration during lymph node transit

    Am. J. Physiol.

    (1982)
  • M.A. Swartz et al.

    Transport in lymphatic capillaries: I. Macroscopic measurement using residence time distribution analysis

    Am. J. Physiol.

    (1996)
  • D. Negrini et al.

    Contribution of lymphatic myogenic activity and respiratory movements to pleural lymph flow

    J. Appl. Physiol.

    (1994)
  • H. Schad et al.

    The significance of respiration for thoracic duct flow in relation to other driving forces of lymph flow

    Pfluegers Arch.

    (1978)
  • R.J. Parsons et al.

    The effect of the pulse upon the formation and flow of lymph

    J. Exp. Med.

    (1938)
  • W.L. Olszewski et al.

    Flow and composition of leg lymph in normal men during venous stasis, muscular activity and local hyperthermia

    Acta Physiol. Scand.

    (1977)
  • E. Ikomi et al.

    Fluid pressures in the rabbit popliteal afferent lymphatics during passive tissue motion

    Lymphology

    (1997)
  • F. Ikomi et al.

    Effects of periodic movement on lymph formation in the rabbit hindlimb

    Microcirc. Ann. Jpn. Soc. Microcirc.

    (1994)
  • J.G. McGeown et al.

    Effects of varying patterns of external compression on lymph flow in the hindlimb of the anaesthetized sheep

    J. Physiol. London

    (1988)
  • J.N. Benoit et al.

    Characterization of intact mesenteric lymphatic pump and its responsiveness to acute edemagenic stress

    Am. J. Physiol.

    (1989)
  • W.L. Olszewski et al.

    Intrinsic contractility of prenodal lymph vessels and lymph flow in human leg

    Am. J. Physiol.

    (1980)
  • A.J. Grodzinsky. Fields, Forces, and Flows in Biological Tissues and Membranes. Massachusetts Institute of Technology...
  • R.L. Jackson et al.

    Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes

    Physiol. Rev.

    (1991)
  • J. Levick

    Flow through interstitium and other fibrous matrices

    Q. Rev. Exp. Physiol.

    (1987)
  • A.J. Grodzinsky

    Electromechanical and physicochemical properties of connective tissue

    Crit. Rev. Biomed. Eng.

    (1983)
  • Cited by (578)

    • Numerical studies of the lymphatic uptake rate

      2023, Computers in Biology and Medicine
    View all citing articles on Scopus
    View full text