Unraveling the mysteries of the lymphatic system.

Updated: May 9, 2019

For many decades the lymphatic system was the forgotten circulatory system. Currently the study of Lymphology is experiencing its Renaissance. More has been learned about the lymphatic system in the last 5-15 years than in the 100 years before. With advances in lymphatic imaging, DNA assays, inflammatory and molecular markers we begin to unravel and understand this complex and amazing system. Emerging evidence demonstrates the vital role the lymphatic system has to play in our health and the onset of disease including obesity, arteriosclerosis, autoimmune diseases, problems with wound healing and cancer.

Following is a snap shot from our full scientific review... head over to our blog for the full article.

Microscopic view of Hepatic Lymphatic Vessel

Starling's & Fick's Law: Theories Revisited

Starling's Law and Fick's Law modelled the movement of fluid and solutes between cardiovascular capillaries and the interstitium based on hydrostatic and oncotic pressure gradients.

Past Understanding:

  • 8 litres of fluid filtration occurred at the capillary bed over a 24 hour period

  • approximately 90% reabsorbed into the venous network (Tortora, 2014).

  • 10% picked up by initial lymphatic vessels.

Present Understanding

  • Recent research indicates all interstitial fluid (100%) under normal conditions that leaves the cardiovascular system at the capillary bed is returned through the lymphatic system (Adamczyk et al, 2016).

  • Approximately 40% of the fluid within lymphatic vessels (Lymphatic load) is returned to the venous circulation through veins connected to lymph nodes (Cooper et al, 2016; Huxley & Scallan, 2011; Keast et al, 2014).

New understanding into forces effecting contractile function.

Lymphangions are the intrinisic (active) pump inside lymphatic vessels. These are small muscular units found within larger collecting lymphatic vessels The lymphatic system also relies on pressure gradients within the blind ended initial lymphatic vessels, which draw fluid into them like straws. The negative pressure within these vessels aids in movement of fluid deeper into the network of larger vessels. Once reaching the collecting vessels positive pressure is created by lymphangions with their synchronised peristaltic contractions. The pulse rate of the lymphatic system is about 5-8 beats per minute with a systolic pressure of 3-5 mmHg and diastolic pressure of 0-1mmHg (Chikly, 2017). This makes the pumping of the lymphatics undetectable to feel or observe without imaging techniques. As seen in the video below using tracer dyes and near infrared light provide real time insight into how this system performs in health and disease. This video below demonstrates the bolus of lymphatic fluid as it moves from one lymphangion unit to the next within deeper collecting vessels.

Emerging Evidence

  • Animal studies have established that lymphangion muscular structure is unique as it has properties of both smooth and striated muscle. This unique combination allows for lymphangions to have similar alterations in contractile activity and tone as vascular smooth muscle with stimulus such as pressure changes, vasoactive substances, mechanical and neuro-modulatory factors. However the striated muscle allow for rapid changes in contractile force and pace in response to pressure on the walls of lymphatic vessels created by changes in fluid load (Chakraborty et al, 2015).

  • Lymphangions can alter the frequency or strength of contractions. Lymphangions alter their function in response to how quickly their muscular segments are filling with fluid as well as how much fluid there is inside the vessel or in the interstitium. This is detected by pressure or stretch exerted on the muscular walls (Chakraborty et al, 2015; Huxley & Scallan, 2011; Gashev et al, 2010).

Acute Inflammation, Chronic Inflammation and Oedema: What's the connection?

The Lymphatic system exhibits great plasticity to remodel itself. Evidence reports on the important role the lymphatic system has in resolving acute inflammation through activation of lymphatic vessels. This process is mediated by the interplay between many chemical mediators as well as mechanical stresses. These forces influence lymphatic vessel hyper permeability, hyperplasia, lymphangiogenesis, involution and remodelling. Nitric Oxide (NO), VEGF-A along with VEGFR-3, VEGF-C and VEGF-D are some of the cytokines that mediate this process. Along with mechanical stresses on the tissue caused by the fluid itself. (Goldman, et al, 2007; Huggenberger et al, 2011; Adamczyk et al, 2016).

Emerging Evidence

  • Immediately after injury there is a temporary lymphatic insufficiency caused by lymphangion reflux (inefficient filling and emptying) which appears to be mediated by NO.

  • Interestingly for the first 4 hours these effects are systemic. This is hypothesised to facilitate immune functions ensuring that pathogens do not move beyond the regional lymphatics and lymph nodes.

  • Decreased contractile activity local to the injury is observed for up to 3 days with normal function returning by 7 days post injury.

  • These studies did note that there are anatomical variations in these responses and that these observations should be investigated in more depth.

  • Increased density of lymphatic vascular networks through lympangiogenesis and hyperplasia are not observed during the first 7 days, however the vessels in the area are dilated, and hyper permeable.

  • This points to theories that acute inflammation that resolves after 7-10 days is mostly facilitated by vascular repair and remodelling of existing lymphatic architecture as well as return of normal contractile function (Lachance et al, 2013; Aldrich & Sevick-Muraca, 2013).

Chronic inflammation and oedema is a self perpetuating cycle that can occur if acute inflammation and oedema fail to resolve. The effects of a lymphatic system under stress can also have systemic effects impacting on other organs and tissues. This has been observed in links between lymphatic dysfunction and chronic inflammatory skin conditions as well as inflammatory bowel disease, rheumatoid arthritis, obesity, and asthma (Huggenberger & Detmar, 2011; Varricchi et al, 2015).

  • Fluid with high protein content and pro-inflammatory cell and chemical content will result in continued oncotic pull of fluid to the area. Over time the development of fibrosis (scarring) can also trap fluid within the area.

  • Lymphatic vessel contractile function is further affected by the presence of pro-inflammatory cells and mediators resulting in decreased effectiveness or cessation of lymphangion pumping altogether (Chakraborty et al, 2015)

  • TGF-B which is known to cause tissue fibrosis during chronic inflammation also exhibits inhibitory effects on Lymphatic endothelial cells and inhibits lymphangiogenesis. Lymphatic vasculature that is produced is hyper permeable, disorganised and incompetent (Clavin et al, 2008; Varricci, et al, 2015).

  • Dysfunctional and incompetent lymphatic system also has negative effects on immunity. including increased risk of infections, development of chronic diseases including arteriosclerosis, inflammatory bowel diseases and cancer (Adamczyk et al, 2016; Yuan et al, 2019; Lund et al, 2016)

Lymphatic Dysfunction: Plumbing problem or inflammatory condition?

Up until recently conditions that result in oedema have been managed as primarily problems of poor plumbing. Clinically this has translated to using techniques such as MLD and compression to move fluid out of the affected area. Whilst these will remain to be two of the four pillars of managing chronic oedema along with skin management and physical activity, new targets for therapy are emerging. The main focus is now on the interplay in inflammatory cells and mediators in lymphatic dysfunction. Investigation continues into their effects on lymphatic vascular regeneration, remodelling, contractile function as well as tissue fibrosis and how all of these contribute to chronic oedema formation. Potential targets for therapy include Lymphatic endothelial cell specific markers including VEGFR-3, VEGF-C and D, Lieukotriene B4 as well as genes that may predispose individuals to lymphatic dysfunction. Multiple trials have been conducted using NSAIDS including Ketoprofen as well as T-cell immunosuppressive drugs (Tacrolimus). These studies reported positive effects in the management of lymphatic dysfunction. However continued research is undergoing in this field in order to understand the possible clinical applications of these findings (Liao & von der Weid, 2014; Dietrich et al, 2014; Jiang et al, 2018; Lund et al, 2016; Tian et al, 2017; Rockson et al, 2018; Gardenier et al, 2017).

Implications: Research to Clinical Practice

Most of the research reported in this review is obtained from animal studies. It is therefore important to follow findings that emerge in the following years and translation to human models. Current understanding in how lymphatics pump, the effects of chronic inflammation within skin, as well as conditions that may affect the ability to resolve inflammation and oe