Lymph flow modulation: the tricks of a performant machinery

Abstract

The lymphatic system displays two unique and remarkable features: (a) it collects excess fluid from interstitial compartments whose pressure is mostly subatmospheric and propels the newly formed lymph against a pressure gradient back into the venous vascular bed; and (b) it adjusts its own activity to cope with the specific draining requirements of the tissue in relation to the microvascular filtration rate. These two targets are achieved through the development, within a single functional lymphatic unit, the lymphangion, of cyclic pressure waves that may either drive interstitial fluid into the lymphangion, allowing lymph formation, or squeeze the lymphangion content through the unidirectional intraluminar valves, thus sustaining centripetal lymph propulsion. Hence, two key questions in the unveiling of the secrets of the lymphatic system are how are intraluminar pressure waves generated and how can they be modulated in response to increased tissue fluid volume? Two mechanisms have been proposed (Aukland & Reed, 1993; Schmidt-Schonbein, 1990): (a) the extrinsic, or passive mechanism, which consists in the transmission of mechanical tissue forces elicited by cardiogenic or respiratory displacements or skeletal muscle contraction to the lymphatic vessel wall; and (b) the intrinsic mechanism, which consists instead in the spontaneous contraction of lymphatic smooth muscle cells triggered by phasic action potentials arising in pace-maker smooth muscles cells dispersed in the vessel wall (McHale & Roddie, 1976; McHale & Meharg, 1992). Under conditions of increased tissue fluid volume, both the contractile force and frequency may be modulated according to the tissue drainage requirements, up to attainment of maximal lymph flow at which tissue oedema eventually develops. Modulation of lymphatic tone and pump function has been attributed to various substances released by lymphatic endothelial cells in response to increased lymph flow and shear stress. According to Gashev et al. (2002 and 2004), increased shear stress in mesenteric and thoracic lymphatic ducts reduces end-systolic tone, ejection fraction and pumping frequency. Such a negative inotropic and chronotropic response was attributed to the shear stress-dependent release of nitric oxide (NO), which determines relaxation of the smooth muscle cells and flow-dependent vasodilatation. A completely different scenario was proposed by Koller et al. (1999). In small iliac lymphatic vessels, they found that higher perfusion pressure gradients determined an increased end-diastolic and end-systolic tone, leading to reduced amplitude of the diameter oscillation during the contractile phase, coupled with increased contractile frequency. This response implies a progressive increase in viscous resistances with increasing lymph flow, is abolished by removal of the lymphatic endothelium and depends upon prostaglandins and tromboxane, but not NO, release. The controversy between these two views is not trivial and concerns several aspects of the strategy adopted to modulate lymph function: (a) is the overall tone and flow resistance decreased or increased with high flows? (b) is high flow attained with stronger and energetically more expensive active pumping or with passive, low resistive vasodilation? (c) is the cellular response to increased flow fast (NO-mediated) or slow (prostanoids-mediated)? and, finally, (d) does the extrinsic mechanism play any role? A significant contribution to clarifying these intriguing questions is provided by Gasheva et al. (2006) in this issue of The Journal of Physiology. In this rigorous study, phasically active and phasically non-active segments of rat thoracic duct were challenged with increasing transmural pressures at no imposed flow, in the presence of the NO inhibitor l-NAME, or the cyclooxygenase inhibitor indo-methacine. Since local intraluminar fluid fluxes are generated in the lymphangion of the phasically active segments due to their own spontaneous contractile activity, this study allows the detection of the self-modulatory response of the lymphatic machinery to the shear stress generated by the intrinsic activity itself. Their data clearly demonstrate that, at any distending pressure, phasically active segments display, compared to non-contracting ones, a lower resting tone accompanied by a more efficient pumping amplitude during the contraction phase. This behaviour is entirely dependent upon NO release, while eucosanoids do not seem to be significantly involved. This finding implies that the lymphatic system attains the required efficiency by exploiting a combination of intrinsic and extrinsic mechanisms, thus attaining a high flow with reduced energy expenses. This new paradigm opens new questions concerning the mechanisms by which mechanotransduction of external tissue forces acting on the lymphatic wall and internal shear stress interfere with the self-regulatory intracellular pathways in order to achieve the required pumping efficiency. Hence, this elegant study by Gasheva et al. (2006), while providing some convincing answers, opens new perspectives on the function of the last almost unexplored section of the cardiovascular system.