Lymphovenous Canada:
Scientist Pierre-Yves von der Weid "pumps" the lymphatic system for answers to its mysteries

I've been working at the University of Calgary since last November. My specialty is the physiology of lymphatic vessels and their pumping process.

I ended up in Calgary after the job I was working in Geneva, Switzerland came to an end. Here in Calgary they were looking for somebody to work in an inflammation-related field. I thought it would be interesting to orient my research on lymphatic vessels to this field, so I applied and was lucky to get the position.

Before that, I was working in Geneva on vascular system biology, looking at the interaction between the endothelium (the layer of cells that lines the cavity of the heart, blood and lymph vessels and cavities of the body) and the smooth muscle in blood vessels. I met a scientist from Australia - Dirk Van Helden - who was looking at the electrical mechanics that are generating pumping in lymphatic vessels. I went to Australia and spent two years working with Dirk in this area during a post-doc. It was not only interesting, but very successful and a lot of fun.

From 1995 until I came to Calgary I worked in Prof. Jean-Louis Bény's lab in Geneva on my own project involving the lymphatic vessels. It's a fascinating field. I had a small grant, and I didn't have anybody working with me, so I spent all my time doing research on lymphatic vessel electrophysiology. It was an interesting period.

My work at the moment is really fundamental science. Once we understand how lymphatic vessels pump, we can start looking at drugs that may improve this process and develop treatments for people who are born with lymphedema or develop it later in life, for example.

There's a lot of mysterious aspects to it and I am really pleased that there are people out there that are trying to increase the perception of this system to the general public.

There aren't a lot of people working in lymphatics to improve our understanding of how the lymphatic system works. A couple of scientists here in Canada - Professor Miles Johnston and Professor Jack Hay - are working in this area. But there are not that many scientists specifically working in the area of lymphatic pump action. There's a good lab in Belfast working on the problem. There is also a group in Japan doing work on lymphatics but I am not sure if they are still looking at the electrical behavior of lymphatic pumps.

What I'm doing now is looking at the electrical potential difference between the inside of lymphatic cells and the area outside of these cells. This difference in potential determines, in every cell what is called a membrane potential. The membrane potential is important, especially in cells that are excitable, like muscle cells. Changes in the membrane potential level lead to changes in the state of contraction in these cells. In lymphatic vessels, small electrical events that modulate the membrane potential are proposed to initiate the pumping.

I am particularly interested in how inflammatory agents (mediators) work on lymphatic pumping. These are substances that are released during an inflammation.

What is known about inflammation and lymph flow is that when you have an inflammation, there's an increase in the interstitial fluid (the liquid that surround the tissues). That's creating an edema that causes an increase in lymph flow. That's one of the major activators of lymphatic pumping. A lot of the known inflammatory mediators have an effect on lymphatic pumping. They all affect the electrical behaviour of the cells in the lymphatic vessels. What I am looking at is if they are affecting the electrical events that are generating the pumping.

How far away do I think scientists are to understanding the pumping aspect of the lymphatic system in terms of being able to actually help people who have a condition in terms of drugs? I can anticipate understanding how it works in the system I'm looking at, but it may not work the same in all lymphatic vessels.

If you're making a comparison with what has been found in blood vessels, where each of them is responding differently to drugs or to mediators, you can make that supposition. Lymphatic vessels may react differently in different parts of the body - but not a lot of people have been looking at it.

Down the road there may be drugs that we are able to identify that enhance the pumping of lymphatic fluid - maybe drugs that are already on the market for other purposes. The problem with that is that when you're using an anti-hypertenser for example, what is the effect of this drug on the lymphatic system? If something is able to decrease blood pressure, is it decreasing lymphatic flow too? Is that a good thing, or should we be applying drugs to increase the lymphatic flow?

What is the effect of other drugs you're using? What is the effect of anti-inflammatory drugs you're using? One purpose of those drugs is to diminish the edema. They are doing that by reducing what is called the capillary filtration. That's one way to diminish the edema. Is it consistent with what the lymphatic system or lymphatic vessels are doing, or is it impairing their function?

As far as I know, they are also decreasing the lymphatic pumping. So they are going in the reverse direction. Decreasing the edema on one side, and diminishing the ability to decrease the edema on the other side - this needs more fine-tuning. It's important to find a kind of balance or to understand what is important in maintaining the balance.

If you prescribe drugs, you may improve the function of the organ you are looking at, but the drug affects the entire body. What happens when you take a drug that affects blood flow? Because lymphatic vessels are made of the same kind of cells as blood vessels, I'm pretty sure that some of the drugs that are used to help cardiovascular problems may well work on lymphatic pumping.

Coming back to inflammation, I will choose an example to illustrate the complexity of the situation. Histamine is a substance that is released by certain cells of the body during inflammatory or allergic reactions. It is involved in the swelling that appear during these reactions. If there is swelling, it should increase lymphatic pumping by itself. But histamine is doing that also, acting directly on the lymphatic vessels. If you're giving an anti-histaminergic, you're reducing the inflammation, you're reducing the swelling, but you're reducing the pumping, too.

It's a really complicated field, and what I'm trying to do at the moment is just to look at the problem from one side, because I'm using a preparation that is isolated from the other components of the system, where only lymphatic vessels are present. So, testing histamine or anti-histaminergic drugs, for example, I am looking at their effect on the lymphatic vessel itself. Then I will be able to compare that with what is observed when the lymphatic vessels are in their normal environment with the other components around.

Students working with me are looking at the effect of histamine in lymphatic vessel preparations. It's not easy to interpret the results, because histamine is acting on a lot of different receptors. Those receptors can be located on the smooth muscles or the endothelium and have a different effect on the lymphatic function, depending on the preparation or dosage. A small change can make all the difference in the world.

RELATED PUBLICATIONS

Van Helden, D. F., von der Weid, P.-Y. and Crowe, M. J. (1995). Electrophysiology of lymphatic smooth muscle. In: Interstitium, Connective Tissue, and Lymphatics (Bert, J., Laine, G.A., McHale, N.G. Reed, R. and Winlove, P., eds), Portland Press, London, pp 221-236.

Van Helden, D. F., von der Weid, P.-Y. and Crowe, M. J. (1996). Intracellular Ca²⁺ release: a basis for electrical pacemaking in lymphatic smooth muscle. In: Smooth Muscle Excitation (Tomita, T. and Bolton, T. B., eds), Academic Press, London, pp 355-373.

von der Weid, P.-Y., Crowe, M. J. and Van Helden, D. F. (1996). Endothelium-dependent modulation of pacemaking in lymphatic vessels of the guinea-pig mesentery. J. Physiol., 493, 563-575.

von der Weid, P.-Y. and Van Helden, D. F. (1996). Beta-Adrenoceptor-mediated hyperpolarization in lymphatic smooth muscle of guinea pig mesentery. Am. J. Physiol.,; 270, H1687-H1695.

Crowe, M. J., von der Weid, P.-Y., Brock, J. A. and Van Helden, D. F. (1997). Co-ordination of contractile activity in guinea-pig mesenteric lymphatics. J. Physiol., 500, 235-244.

von der Weid, P.-Y and Van Helden, D. F. (1997). Functional electrical properties of the endothelium in lymphatic vessels of the guinea-pig mesentery. J. Physiol., 504, 439-451.

von der Weid, P.-Y. (1998). ATP-sensitive K⁺ channels in lymphatic smooth muscle of the guinea-pig mesentery: Role in nitric oxide and beta-adrenoceptor agonist-induced hyperpolarizations. Br. J. Pharmacol., 125, 17-22.

Van Helden D.F., Imtiaz M.S., Nurgaliyeva K., von der Weid P.-Y. and Dosen P.J. (1999). Role of Intracellular Ca²⁺ release in generation of slow waves in the guinea-pig gastric pylorus. J. Physiol von der Weid, P.-Y, Zhao, J. and Van Helden, D.F. (2000). Nitric oxide decreases the pumping pacemaker activity in lymphatic vessel of in the guinea-pig mesentery. Am. J. Physiol, submitted.