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Reviews: Unraveling the mysteries of the lymphatic system.

For many decades the lymphatic system was the forgotten circulatory system. The cardiovascular system in comparison to lymphatics has received more funding and has been more greatly researched to establish understanding of its nature and relationships with other systems, organs and tissues of the body in health and disease (NIH, 2018; Heart Foundation, 2017; Lympoedema Action Alliance, 2018). Its easy to understand why this was the case. After all, the cardiovascular system is responsible for delivery of nutrients essential for life to every cell within the body. Cardio vascular networks are developed very early on in embryology and by day 22 the heart starts beating. For many people (though debated) life is considered to begin with this event. Its only after the cardiovascular system is functioning fully that the lymphatic system begins to develop in week 6-7 of gestation.

The study of Lymphology is now experiencing its Renaissance. More has been learned about the lymphatic system in the last 5-15 years than in the 100 years before. Why is this so? Lymphatics by their very nature are almost invisible. The fragile vessels collapse after death and become virtually invisible unless the anatomist knows what they are looking for. Lymph fluid is clear and nondescript to the naked eye. 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 lymphatic system is no longer simply defined by its task of cleaning up after its more glorified cousin, the cardiovascular system. Looking at this system more closely has revealed it has a much more vital role to play in our health and the onset of disease including obesity, arteriosclerosis, autoimmune diseases, problems with wound healing and cancer.

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. Most anatomy and physiology books presented, based on these models, that 8 litres of fluid filtration occurred at the capillary bed over a 24 hour period with approximately 90% reabsorbed into the venous network (Tortora, 2014). However, evidence indicates that the exchange between arterioles, venules and lymphatic vessels is a much more dynamic and complex process than these models demonstrate. Some research even goes so far to say that all fluid (100%) under normal conditions that leaves the cardiovascular system at the capillary bed is returned through the lymphatic system (Adamczyk et al, 2016). This is due to the modulation of blood vessel permeability and diameter in response to the loss of fluid and proteins. This adjustment ensures stable pressure within the cardiovascular system. 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). However reabsorption of interstitial fluid has been found to occur within arterioles, venules, capillaries and initial lymphatic vessels. The complex interplay of hormones, inflammation and physical forces at tissue level and their effects on vessel permeability are still emerging (Huxley & Scallan, 2011; Negrini & Moriondo, 2011).

New understanding into forces effecting contractile function.

Lymphatic fluid movement relies on a combination of intrinsic (internal or active) and extrinsic (external or passive) mechanisms. Intrinsic and extrinsic forces together provide propulsion of fluid and molecules within the lymphatic system from the initial lymphatics, against gravity to be returned at the subclavian veins, thoracic and lymphatic ducts (Chakraborty et al, 2015; Huxley & Scallan, 2011; Gashev et al, 2010)

Within the larger lymphatic vessels (collectors) found within subcutaneous tissue, small muscular units are found along with bicuspid valves. These units are called Lymphangions (little hearts). The heart is strong enough to propel blood through the entire cardiovascular network, with loss in pressure once reaching the venous system. At this point assistance against gravity to return blood to the heart is facilitated by muscle contractions as well as bicuspid valves within the veins to facilitate uni directional flow. The lymphatic system relies on hydrostatic alterations (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, new imaging using tracer dyes and near infrared light provide real time insight into how this system performs in health and disease. These techniques can also be used to evaluate the effects of interventions such as MLD and compression on lymphatic flow. This video below demonstrates the bolus of lymphatic fluid as it moves from one lymphangion unit to the next within deeper collecting vessels.

Greater understanding into the intricacies of lymphatics are emerging consistently with the greater amount of research into this field currently. Animal studies have established that lymphangion muscular structure is unique. The muscle that facilitates forward propulsion through lymphatic vessels is different to both smooth and cardiac muscle, 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).

Lymphatic contractile activity is an area currently receiving greater attention in research. As understanding how, when and why lymphangions change their function is important to understand acute inflammation and how it resolves, as well as why chronic oedema and lymphoedema may develop. It has been observed that lymphangions can alter the frequency (Chronotopic) or strength (Inotropic) 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).

The initial response to increased fluid load is to increase the frequency (speed) of contractions. If the fluid load persists increased strength (force) of contractions will be initiated and finally discontinuation of contractile function altogether in order to conserve energy. This occurs when the rate of fluid flow no longer requires contractions for forward propulsion. It can be likened to having a flood coming into your house. Initially you will madly try to bucket the water out, when that fails you may go and get some bigger buckets and more people to help. Then if the flood waters continue to rise you will just stand back and put your hands up and save your energy. When the waters start to recede again you will start bucketing out the remainder. This also occurs with lymphangions as well. Stretch receptors signal that the lymphangion units are no longer under pressure and contractile function will begin again. This event is important in order to create the hydrostatic pressure gradient within segmental muscular units to pull fluid from the superficial network into the deeper system (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 or ability to change and remodel itself. Evidence reports on the important role the lymphatic system has in resolving acute inflammation. In early inflammation histamine, bradykinin, TNF, and IL-6/IL-8 increase blood vessel permeability and vasodilation. This is necessary to allow following cellular processes to facilitate healing. During this process fluid and proteins move into the interstitium resulting in oedema. At this stage fluid is not bound by the ECM and is soft and easy to mobilise (Villeco, 2012). Activation of lymphatic vessels is now believed to resolve inflammation. This process is mediated by the interplay between many chemcial mediators as well as mechanical stresses. These forces influence lymphatic vessel hyper permeability, hyperplasia, lymphangiogenesis, involution and remodelling. VEGF-A along with VEGFR-3, VEGF-C and VEGF-D, are some of the cytokines that mediate this process. They exert effects promoting lymphangiogenesis, lymphatic hyperplasia and regulate remodelling along with MMP's (Huggenberger et al, 2011; Adamczyk et al, 2016). Animal studies have demonstrated chemicals such as Nitric Oxide (NO) produced by endothelium during inflammation also play a role in activating alterations in lymphatic contractile pumping (Chakraborty et al, 2015). Other studies have reported that the fluid itself and the pathways through interstitium creating mechanical stresses on the tissue, is a mechanism that contributes to organisation of lymphatic vessel remodelling (Goldman, et al, 2007).

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. This has implications for why acute oedema is observed to "peak" at this period and then should be observed to dissipate (Aldrich & Sevick-Muraca (2013; Lechance, Haze & Sevick-Muraca, 2013). These studies did note that there are anatomical variations in these responses and that these observations should be investigated in more depth. Density of lymphatic vascular networks (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).

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 chronic inflammatory skin conditions as well as inflammatory bowel disease, rheumatoid arthritis, obesity, and asthma (Huggenberger & Detmar, 2011; Varricchi et al, 2015). Oedema with its high protein content and pro-inflammatory cell and chemical content will result in continued oncotic pull of fluid to the area and over time the development of fibrosis (scarring) caused by chronic inflammation. This process can also trap fluid within the area by binding water to ECM components and creating a physical barrier to moving fluid. 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) These factors combined mean that fluid that is bound and trapped can no longer be removed by lymphatic vessels (Villeco, 2012). Clinically this is observed by pitting or non-pitting oedema. 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). The flow on effects of a dysfunctional or incompetent lymphatic system and remodelling process is the negative effects on immunity. These negative effects can be observed both locally at the site of chronic oedema or lymphoedema, as well as systemically. There are well documented links between chronic inflammation and dysfunctional lymphatic remodelling with increased risk of infections, development of chronic diseases including arteriosclerosis, inflammatory bowel diseases and cancer. This in part is due to problems with dendritic and other immune cells reaching lymph nodes so that functions of surveillance, innate and adaptive immunity can take place (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. This is due to understanding that the lymphatic and venous systems become overwhelmed and fail in many conditions of chronic oedema, including acquired (secondary) lymphoedma and lymphovenous oedema. It has been observed that these conditions present with damage to the vessels and valves, incompetence or failure of the pumping mechanisms and progressive tissue alterations including fibrosis. Clinically this has translated to using techniques such as MLD and compression to move fluid out of the affected area. Whilst these are still two of the four pillars of managing chronic oedema along with skin management and physical activity, new targets for therapy are emerging. These therapies are based on an emerging understanding of the underlying pathophysiology and variances in pathogenesis of chronic oedema formation. 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 as well as genes that may predispose individuals to lymphatic dysfunction. However, another interesting target emerged in 2017, when a Stanford research group released news that they had found a pharmaceutical drug capable of treating and reversing lymphoedema (Click Here). This study from two labs in America identified the role of Leukotriene B4 in the pathogenesis of lymphatic dysfunction. Since then 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. Further evidence of the effects of using new targets for therapy, such as molecular markers in the skin for lymphatic vessels and their effects on lymphatic plasticity, as well as the clinical application in managing oedema and inflammation is going to be of interest to dermal therapy practice.

However presently, it is important to be educated on current literature into how lymphatics pump, the effects of chronic inflammation within skin, as well as conditions that may affect the ability to resolve inflammation and oedema. This will assist the Dermal Clinician/Therapist to manage inflammation, wound repair and oedema to prevent complications in the future based on current evidence and science. Clinical studies and case studies that evaluate practice against research are important to build knowledge in practical application and translation of research to the bedside. Questions we may want to evaluate include: when is the best time to implement manual lymphatic drainage (MLD) after an injury? In what situations is it better practice to use compression? Are their topical formulations or modalities that can aid in lymphatic regeneration and function? In the next blog the ASDC Education team will provide insight into how oedema can be assessed and managed, informed by current best practice and the latest evidence.

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