To the interstitial space - and beyond!

Abstract

In clinical practice, the elements of the circulation that receive most attention are the heart and blood vessels, despite the fact that ‘the heart and vasculature exists for one fundamental purpose: the delivery of metabolic substrate to the cells of the organism’ (Levick, 1991). Attitudes to this ‘fundamental purpose’ vary. The book cited here assigns nearly 20% of its text to these processes, although another similar basic textbook devotes a mere 5%, and generally the emphasis in medical teaching is on the arterial side of the circulation. One of the reasons for this blind spot may be that scientists, and clinical scientists in particular, tend to study features that are accessible, where equipment and methods are available, and where interest already lies. Thus despite the common definition of shock as ‘where vital tissues are inadequately perfused’, consideration of the processes that govern exchange from the capillary to the cell, and interest in the regulation of the medium in which this exchange occurs, are remarkably limited in clinical science. The lymphatic tree that flows from the tissues is a challenge to our knowledge. Its function may in many respects mirror the better known vasculature: it has mechanical, hydraulic and regulatory systems that are vital to tissue life, and indeed there may be some very analogous control of blood and lymph vessels. Because of the impression that most intensive care considerations focus on the blood system, a Journal of Physiology symposium entitled ‘Physiology, pharmacology and pathology of tissue fluid exchange’ was held at the 31st International Symposium on Intensive Care and Emergency Medicine in Brussels, Belgium, on 22 March 2011, to encourage clinicians to lift their eyes from the bloodstream to the horizon of the tissues, and consider these vital processes in the interstitial space. Oedema is recognised as a marker and a consequence of disease, one of the cardinal signs of inflammation, and one of the classic signs of cardiac failure: but lymphatic processes continue (or fail) unseen. The contributions from the symposium published in this issue of The Journal aim to encourage consideration of the wider aspects of tissue fluid, and perhaps stimulate research and therapy in these topics. The structure and mechanical behaviour of the lymphatic channels is fascinatingly diverse. Negrini & Moriondo (2011) explain how lymphatic vessels and their surrounding tissues interact to provide a range of different characteristics, and sustain varying functions that contribute to the formation, modification, and transport of lymphatic fluids. In particular, their analysis illustrates how changes in tissue activity can impact on the drainage of tissue fluid, and may offer some additional therapeutic reasons for aiming to sustain respiratory muscle activity during critical illness. The factors that control lymphatic exchange have some interesting parallels with the better known capillaries. Huxley & Scallan (2011) have studied lymphatic exchange and transport processes. Their review considers the structures and forces that affect and regulate fluid and protein exchange, and emphasises how these can be very actively regulated. These regulatory factors include structure and activity of the vessels themselves, and responses to mediators that substantially affect circulatory dynamics, such as ANP and cytokines. These agents affect both mechanical activity and permeability, often in different ways. If we include the heterogeneity of the lymphatic vessels in this mix, then it's clear that this is, in health, a finely balanced medium where the potential for disruption by disease is considerable. It also may well be that some the agents currently used to manage the circulation could have substantial effects on lymphatic function. The review by Wiig (2011) extends these considerations to some pathological scenarios: vascular overload and sepsis. He emphasises the diversity of the composition of interstitial fluid, the different physicochemical features of the interstitial matrix, and the capacity of the gradients in composition to be altered by dynamic processes such as a change in filtration rate. Even a remarkably effective regulation of interstitial fluid, as found in the trachea, can be disrupted by fluid overload, as well as by other forms of damage such as neurogenic inflammation. Local paracrine factors are also highly important in tissue fluid formation, as he shows in considering experiments using the lymph circulation through the spleen. The spleen generates a large lymph flow and liberates not only formed elements but also soluble mediators such as cytokines. Sepsis magnifies these processes. Responses in these two tissues, spleen and trachea, differ substantially, showing that epithelial tissue has an important part to play in cytokine output. Overall, these reviews emphasise how vital it should be that we study what is important rather than what we can study easily. On this new horizon, we can only speculate what therapeutic targets may emerge, but the signs are that there may be many, and varied, approaches that may be taken in managing this vital medium, the interstitial fluid.