Inflammation and fibrosis in lymphoedema. What's really going on and does MLD help?

Updated: Oct 14


We know that CDT (combined decongestive therapy) which includes MLD, multi-layer bandaging, exercise and skin-care, can reduce oedema. It also has a beneficial effect on fibro-sclerosis and if applied early enough, fibrosis can be prevented. If fibrosis is already present,

CDT will significantly reduce the extent of the fibrotic induration.

While there are multiple studies showing that MLD & CDT reduce the symptoms of inflammation and can reverse some fibrotic changes, there is very little in the literature to identify the molecular processes that determine either the accumulation of fibro-sclerotic tissue changes, or their reduction under CDT.

Dr Prof Michael Foeldi. image from www.eurolymphology.org/remembering-prof-foldi

The first investigation on this was done in 2000 by Professor Foeldi, one of the most notable pioneers in lymphoedema research (1). The abstract of this seminal paper is pasted below. Dr Foeldi and his colleagues measured several markers for gene expression of molecules associated with inflammation among nine people with lower limb lymphoedema. After phase I CDT there was a reduction of between 42% and 64% in expression of these pro-inflammatory markers. There was also an average reduction of 4.2 litres with one participant reducing in 10.6 litres in one leg and 8.2 litres in the other. It is worth noting here that the Foeldi's use the Dr Vodder MLD techniques in their clinical practice, so this effect cannot be directly extrapolated to treatments which use lymphatic effleurage. Read more about the difference between techniques here.

The relationship between inflammation and lymphoedema has led to other research on anti-inflammatory medication such as ketoprofen (2), but so far the results are weak and have only been shown in mice with early post surgical oedema, not in people with stage 2 or 3 lymphoedema. I posted on this a couple of years ago, as did others, to caution about the side-effects. Drugs like this are not suitable for long term use, but short term use may be beneficial in preventing oedema forming in those most at risk.

Another interesting connection is the relationship between hyaluronic acid (HA) and inflammation (3). In our lymphology classes we discuss the role of HA in creating thixotrophic changes in the ground substance of the extra-cellular matrix, and I have written on this previously in several blogs. Read more about thixotropy at #TalkingLymph

Now it seems HA is also involved in regulating inflammatory processes in the interstitium.


"HA and its binding proteins regulate the expression of inflammatory genes, the recruitment of inflammatory cells, the release of inflammatory cytokines, and can attenuate the course of inflammation, providing protection against tissue damage." (3)

What does all this mean for our MLD & CDT treatments? Until we have more research to build on Professor Foeldi's findings we still have dots missing in our connect-the-dots picture of what is happening at a molecular level during our treatments. What we do know is that our clients experience a reduction in inflammatory symptoms, removal of some fibro-sclerotic tissue changes and a reduced risk of infection.

In light of the known effects of MLD in changing the thixotrophic state of the ground substance, perhaps the effects on inflammation are more that just the removal of inflammatory mediators as we have previously thought?

I'm sure one day will will have the background research to fully explain these undisputed clinical observations.


Read more #TalkingLymph posts on thixotrophy here.


1: Foldi E, Sauerwald A, Hennig B. Effect of complex decongestive physiotherapy on gene expression for the inflammatory response in peripheral lymphedema. Lymphology. 2000;33(1):19-23.


Abstract

Complex decongestive physiotherapy (CDP), consisting of manual lymph drainage, compression bandaging, remedial exercises and skin care, mobilizes accumulated edema fluid and increases lymph flow. On the other hand, it also has a beneficial therapeutic effect on fibrosclerosis. Because little is known of its possible mode of action on a molecular level, this preliminary study evaluated CDP in patients with peripheral leg lymphedema as to the potential role of gene expression in the inflammatory response. The quantitative expression of genes for CD14, interferon-gamma receptor (IFN gamma R), tumor necrosis factor-alpha (TNF alpha), integrin alpha 4 beta 1 (VLA-4), tumor necrosis factor receptor p55 (TNFR1) and CD44 (standard form) was examined in 9 patients with primary or secondary leg lymphedema before and after phase 1 of CDP. Overall, there was a decrease of expression of these pro-inflammatory genes after CDP, suggesting that biologic mechanisms implicated in the inflammatory cascades in other disorders are also involved in the fibrosclerotic reactivity in lymphedema. However, whereas each patient acted as his or her own control before and after CDP, gene expression in normal patients and normal limbs before and after CDP needs to be examined before the full meaning of these observations can be understood


2: Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-Inflammatory Pharmacotherapy with Ketoprofen Ameliorates Experimental Lymphatic Vascular Insufficiency in Mice. PLOS One. 2009;4(12).


Abstract

Background: Disruption of the lymphatic vasculature causes edema, inflammation, and end-tissue destruction. To assess the therapeutic efficacy of systemic anti-inflammatory therapy in this disease, we examined the impact of a nonsteroidal anti-inflammatory drug (NSAID), ketoprofen, and of a soluble TNF-alpha receptor (sTNF-R1) upon tumor necrosis factor (TNF)-alpha activity in a mouse model of acquired lymphedema. Methods and Findings: Lymphedema was induced by microsurgical ablation of major lymphatic conduits in the murine tail. Untreated control mice with lymphedema developed significant edema and extensive histopathological inflammation compared to sham surgical controls. Short-term ketoprofen treatment reduced tail edema and normalized the histopathology while paradoxically increasing TNF-alpha gene expression and cytokine levels. Conversely, sTNF-R1 treatment increased tail volume, exacerbated the histopathology, and decreased TNF-alpha gene expression. Expression of vascular endothelial growth factor-C (VEGF-C), which stimulates lymphangiogenesis, closely correlated with TNF-alpha expression. Conclusions: Ketoprofen therapy reduces experimental post-surgical lymphedema, yet direct TNF-alpha inhibition does not. Reducing inflammation while preserving TNF-alpha activity appears to optimize the repair response. It is possible that the observed favorable responses, at least in part, are mediated through enhanced VEGF-C signaling.


3: Petrey AC, de la Motte CA. Hyaluronan, a crucial regulator of inflammation. Front Immunol. 2014;5:101


Abstract

Hyaluronan (HA), a major component of the extracellular matrix (ECM), plays a key role in regulating inflammation. Inflammation is associated with accumulation and turnover of HA polymers by multiple cell types. Increasingly through the years, HA has become recognized as an active participant in inflammatory, angiogenic, fibrotic, and cancer promoting processes. HA and its binding proteins regulate the expression of inflammatory genes, the recruitment of inflammatory cells, the release of inflammatory cytokines, and can attenuate the course of inflammation, providing protection against tissue damage. A growing body of evidence suggests the cell responses are HA molecular weight dependent. HA fragments generated by multiple mechanisms throughout the course of inflammatory pathologies, elicit cellular responses distinct from intact HA. This review focuses on the role of HA in the promotion and resolution of inflammation.