Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return and swelling of the extremities. Lymphedema is divided into primary and secondary forms based on the underlying etiology. Despite substantial advances in both surgical and conservative techniques, therapeutic options for the management of lymphedema are limited. Although rarely lethal, lymphedema is a disfiguring and disabling condition with an associated decrease in the quality of life. The recent impressive expansion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities for the treatment of lymphedema. This review highlights the lymphatic biology, the pathophysiology of lymphedema, and the therapeutic lymphangiogenesis using hepatocyte growth factor.
The lymphatic vascular system maintains tissue fluid homeostasis, plays a role in the afferent immune response, and carries proteins and large particulate matter away from the tissue spaces [
In addition to draining and transporting fluid, the lymphatic vascular system also plays an important role in the immune response by transporting leukocytes, antigens, and dendritic cells. Lymphatic vessels have many lymph nodes, which act as checkpoints for the immune response. The lymphatic system is also responsible for the absorption of dietary fats and fat-soluble vitamins from the digestive tract, in which specialized lymphatic capillaries (lacteals) in the intestinal villi absorb the lipid particles (chylomicrons) released by enterocytes.
Anatomic or functional obstruction of the lymphatic system can result in the progressive accumulation of protein-rich fluid in the interstitial spaces (lymphedema) [
Despite substantial advances in surgical and conservative techniques, therapeutic options for the management of lymphedema are limited [
The pathophysiology of lymphedema is generally divided into two periods. During the first period, the pathological changes occur mainly only in the lymphatics and in the soft tissues lymphedema symptoms are not apparent (occult lymphedema = Stage 0). After this stage, the pathological changes occur in the soft tissue (fat, connective tissue, skin, etc.) of the limbs, resulting in the progressive swelling caused by systematic and combined pathologic factors. This clinical state is characterized not only by progressive swelling but also by fat and scar deposition, immunosuppression, a propensity for cellulitis, and microvascular proliferation (Figure
Schematic diagram of the pathophysiology of lymphedema.
Congenitally deficient or obstructed lymphatics promote lymph stasis, which is accompanied by deranged truncal contractility, progressive valve incompetence, destruction of contractile elements (lymphangioparalysis), and gradual ectasia of lymphatic collectors. After a variable period (occult lymphedema), a series of events is initiated, culminating in chronic lymphedema. Because of difficulties in diagnosis, the pathophysiology of occult lymphedema is almost unknown for most patients.
When lymphedema is apparent via the pathological changes in the lymphatic system, some findings may be confirmed by images [
Staging according to the “consensus document” of the International Society of Lymphology.
Clinical stage | Evidence |
---|---|
0 | Subclinical with possible clinical evolution |
I | Edema regressing with treatments with positive pitting test |
II | Edema partially regressing with treatments with negative pitting test |
III | Elephantiasis with cutaneous complications and recurrent infections |
These pathological changes in soft tissues are induced by fibrosis and metabolic disorder. At this time, chronic inflammation is recognized as the important mechanism, involving lymphocytes, monocyte/macrophages, and dendritic cells. As previously reported, these inflammatory cells produce many inflammatory cytokines related to fibrosis, such as CTGF, TGF-
Infection and adipogenesis are exacerbation factors of lymphedema. The propensity for recurrent soft-tissue infection is one of the most troublesome aspects of long-standing lymphedema. Accumulated fluid and proteins provide a good substrate for bacterial growth. Lymphatic dysfunction impairs the local immune response, which plays a permissive role in the propagation of bacterial and fungal invasion. Furthermore, once established, soft tissue infection exacerbates the existing lymphatic dysfunction, sometimes irreversibly.
Although the connection between the lymphatic system and fat absorption/deposition has been recognized by clinicians for well over a hundred years, the subject received relatively little interest until recent publications raised theories regarding the mechanism of this association. It has long been recognized that a lymphedematous limb accumulates fat at an increased rate when compared to the rest of the body and that, conversely, when weight loss is undertaken, the lymphedematous limb loses fat at a slower rate than the rest of the body. The underlying cause of these observations is not well understood. A recent publication studying Prox1 haploinsufficient mice proposed that the lymph itself is stimulatory to fat cells [
Three genes were confirmed as the cause of lymphedema [
Although lymphedema is recognized to generally not affect prognosis of mortality, in rare cases, chronic lymphedema may be complicated by the development of malignant tumors. One of these malignancies is lymphangiosarcoma (Stewart-Treves syndrome) [
Recent studies suggest that lymphangiogenesis can be stimulated by various cytokines. For example, vascular endothelial growth factors (VEGF)-C and -D promote lymphangiogenesis by activating the VEGF receptor-3 (VEGFR-3), which is expressed on lymphatic endothelial cells (LEC) [
Hepatocyte growth factor (HGF) was originally identified as a potent mitogen for hepatocytes, and HGF is currently recognized as a mesenchyme-derived pleiotropic factor that regulates growth, motility, and morphogenesis of various types of cells [
We have previously investigated and reported the lymphangiogenic potency of HGF [
HGF lymphangiogenesis and gene therapy for lymphedema. (a) Effect of HGF plasmid on c-fos promoter activity in LEC.
In accordance with
In view of these results, we hypothesized that HGF gene therapy would stimulate the growth of the lymphatic vascular system and alter the course of lymphedema. In terms of HGF gene therapy, the safety of the use of HGF plasmid DNA in patients with critical limb ischemia has been investigated in a prospective open-labeled clinical trial [
The lymphatic vessels have three specific functions for maintenance of homeostasis: (1) drainage of tissue fluid; (2) immunosurveillance; and (3) the uptake of dietary fats. Furthermore, they play an important role in the pathogenesis of several diseases, including cancer, lymphedema, and various inflammatory conditions. Consequently, administration of lymphatic growth factors or related molecules provides the potential to target lymphatic vessels in human disease. In particular, therapeutic lymphangiogenesis is a promising gene therapy strategy for the treatment of lymphedema.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are grateful to Professor N. Azuma and Professor T. Sasajima (Asahikawa Medical University) for kindly supporting their efforts.