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1Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi dell'Insubria, Varese; and 2Dipartimento di Chirurgia, Ospedale San Raffaele, Milan, Italy
Submitted 20 January 2005 ; accepted in final form 15 March 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Ptm = Plymph – Pint) was in favor of lymph formation throughout the whole respiratory cycle (Ptm = –6.8 ± 1.2 mmHg) during spontaneous breathing but not during mechanical ventilation (Ptm = –1.1 ± 1.8 mmHg). Therefore, data suggest that local tissue stress associated with the active contraction of respiratory muscles is required to support an efficient lymphatic drainage from the thoracic tissues.
interstitial fluid pressure; tissue fluid homeostasis
An important factor in enhancing lymphatic function is tissue movement, which determines cycles of external compression/expansion of the lymphatic vessel lumen. As a result, pressure gradients develop across the lymphatic vessel wall favoring both fluid entrance from the interstitium into the lymphatic lumen and/or progression of the newly formed lymph from one functional unit (lymphangion) to the next (1, 22). Hence, the composite effect of the cyclic cardiac and respiratory movements may actually play a significant role in enhancing lymphatic function in thoracic tissues.
Although the importance of the respiratory activity in pleural lymph formation has been demonstrated by indirect evidence (13), the mechanism through which the respiratory component of thoracic tissue movements acts on the lymphatic vessels remains at present unknown, mainly because of the experimental difficulties encountered in approaching the initial lymphatic system "in situ" in highly moving tissues. Therefore, the aim of the present research was to measure the hydraulic pressure in the initial lymphatics draining the thoracic tissues (Plymph) and in the adjacent intercostal interstitial space (Pint) during spontaneous breathing or passive lung inflation. The role of the tensile and/or compressive tissue stresses applied during active or passive chest expansion was evaluated on the basis of the net pressure gradients developing during the entire respiratory cycle across the lymphatic vessel wall.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Blunted-tipped saline-filled plastic catheters were inserted into a carotid artery and a jugular vein and were connected to physiological pressure transducers (model P23 XL; Gould Electronics). In addition, to measure esophageal pressure, a saline-filled PE50 catheter was advanced in the esophagus with its blunted tip positioned in correspondence with the second third of the sternum.
Systemic arterial, venous, and esophageal pressures were monitored throughout the whole experiment by conveying the pressure signal to an amplifier and a signal conditioner (model 6600; Gould Electronics). The signal was then digitized with an analog-to-digital board and displayed on the monitor screen using dedicated LabView software (National Instruments, Austin, TX).
A heated pneumotachograph (model 8420; Hans Rudolph) equipped with a dedicated pneumotach amplifier (model 1110A; Hans Rudolph) was connected to the tracheal cannula for continuous recording of respiratory flow. Tidal volume was obtained from integration of the respiratory flow signal performed with the LabView software.
Intravital labeling of intercostal pleural lymphatic network. The skin and the external intercostal muscles on the right side of the thorax were cleared to expose the ribs and the internal intercostal muscles. A stainless steel cannula (external diameter 0.7 mm; internal diameter 0.4 mm) connected to a plastic catheter and to a three-way stopclock was filled with saline solution containing 20% fluorescent dextrans (FITC; molecular weight 70,000; Sigma, St. Louis, MO). The blunted cannula tip was tangentially inserted into the pleural space while saline was flushed over the insertion point to prevent air entrance into the pleural space, and the cannula was then gently advanced along the lung surface. Subsequently, 0.5 ml of the fluorescent solution was injected intrapleurally, the cannula was withdrawn, and the animal was turned to right lateral decubitus position.
Two hours after FITC injection, the animal was turned back to supine position. The internal intercostal muscle fibers of the parasternal region in the third to seventh right intercostal spaces were carefully removed to expose the lymphatic vessels containing the fluorescent dye and were thus clearly detectable though a stereomicroscope (magnification x60–100; Zeiss SV 11) when illuminated with a fluorescent mercury lamp (light wavelength 425/65 nm, HBO 50 W; Zeiss) as in the example of Fig. 1. The microscope image was captured with a digital video camera (Axiocam; Zeiss), processed with a dedicated board, and displayed on a color monitor with a maximal magnification on the video screen of x200. Digital images on the screen were stored and successively automatically analyzed for vessel dimensions with the use of image analysis software (KS300; Zeiss). The diameter of the visualized and micropunctured lymph vessels computed on the stereomicroscopic images ranged between 
50 and 300 µm.
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Recording of intraluminal lymphatic and interstitial hydraulic pressure.
The hydraulic pressures within the visualized lymphatic vessel lumen (Plymph) and in the adjacent intercostal interstitial space (Pint) were measured by means of the micropuncture technique while the animal was spontaneously breathing though the intratracheal cannula. Pressure recordings were performed using glass micropipettes, with a taper of 150 µm beveled down to a tip diameter of 2–4 µm and filled with 1 M NaCl solution, that were inserted in a pipette holder filled with the same solution. The holder was connected to a mineral oil-filled pressure transducer (Gould Instruments System) motor driven by an electrohydraulic system (Dual Servonull pressure measuring system; Vista Electronics, Ramona, CA). The amplified pressure signal was conveyed and displayed on the monitor screen utilizing the same equipment described for the vascular pressure recordings. Before its use, each micropipette was calibrated in a modified Lucite box by imposing step changes of ±5 mmHg in the box chamber; pipettes displaying a nonlinear calibration in the pressure range ±30 mmHg were discarded. After calibration, pipette holders were mounted in two three-dimensional hydraulic micromanipulators (Joystick Micromanipulator MO-188 or MO-109; Narishighe, Tokyo, Japan) equipped with a fourth micromanipulator movement to drive the tip of the micropipette into the tissue. Electrical zeroing of the recording system was performed before and immediately after each measurement by dipping the micropipette tip in a saline pool positioned at the same height of the pipette insertion point. Criteria for acceptance of the micropipette pressure recordings were 1) an unchanged electrical zero of the system upon withdrawal from the tissue compared with preinsertion value, 2) a stable pressure reading for at least 2 min, and 3) repeated measurements from the same area within 1 mmHg of each other.
In the same animal, up to four paired Plymph and Pint recordings were obtained. After the pipette tip was positioned into the chosen lymph vessel, another pipette was inserted in the adjacent interstitium 10 µm from the outer lymphatic vessel surface. The microsurgical procedure to expose the lymphatics deep in the parasternal intercostal spaces required 30–60 min; hence, measurements of Plymph and Pint began at 150–180 min after dextran injection and 180–210 min after anesthesia induction. On average, experiments lasted up to 6 h, during which the animals were always spontaneously breathing.
In a small group (n = 3), after pressure recording during spontaneous breathing, rats were paralyzed with a single intravenous dose of pancuronium bromide (8 mg/kg) and then passively ventilated (ventilator model 7025; Ugo Basile, Comerio, Italy) with room air, maintaining the same respiratory frequency and tidal volume observed in the previous phase of spontaneous ventilation. Alveolar pressure ranged from atmospheric, at end expiration, to 18 mmHg at end inspiration for a tidal volume of 6 ml (20 ml/kg). A small bolus of anesthetic cocktail was given before paralysis; subsequently, the adequate level of anesthesia was assessed to maintain a stable arterial pressure. Plymph and adjacent Pint were then recorded from the same intercostal vessels where they had been previously recorded during spontaneous ventilation. In most cases, no indication of vessel damage from the previous micropuncture was detectable. However, in a few instances, the first pipette insertion caused a leak in the lymph vessel wall, as indicated by a fluorescent spot in the tissue around the vessel; in this case, the injured area was avoided and micropuncture was performed in a new site in an intact segment of the same vessel. At the end of the experiment the animals were euthanized with an anesthesia overdose.
Data analysis. Data are reported as means ± SE. Absolute values were compared using one-way ANOVA. Differences between mean values were considered significant at P < 0.05. Whenever one-way ANOVA detected a significant difference between mean values, all pairwise multiple comparison procedures were performed (Bonferroni t-test).
The correlation existing between the end-inspiratory (Ptm-I) and the corresponding end-expiratory (Ptm-E) transmural pressure gradient was assessed by performing the Pearson product moment correlation with significance for P > 0.05.
To appreciate the relative importance of cardiogenic and respiratory swings in determining the overall shape of the Plymph and Pint traces, we performed a frequency-domain analysis of the time-domain pressure traces by means of fast Fourier transformation (FFT). Reference frequencies for cardiac and respiratory activity have been obtained from arterial and tidal volume time-domain traces, respectively. FFT of Ptm was performed with Origin software (version 5.0; Microcal Software, Northampton, MA) by segmenting the most stable recordings obtained into blocks of 1,024 samples (10.24 s of recording) and performing a baseline correction for each block to minimize artifactual direct current components.
Stereomicroscopic images were enhanced using Simple PCI software (Compix, Cranberry Township, PA).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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6 h of deep general anesthesia.
In Fig. 2A, typical recordings of Plymph (middle, continuous line) and Pint (middle, dotted line) obtained during spontaneous breathing at 93 cycles /min (1.6 Hz) are presented. The Plymph and Pint traces are characterized by large pressure waves associated with the changes in tidal volume (top) during spontaneous respiratory swings. Small cardiogenic oscillations, associated with cardiac activity and amounting to 0.5 mmHg, also are detectable in the original Plymph trace. In the example in Fig. 2A, the end-expiratory (Plymph-E) and end-inspiratory (Plymph-I) intraluminal lymphatic pressure averaged –0.7 ± 0.2 and –3 ± 0.1 mmHg, respectively, whereas the end-expiratory (Pint-E) and end-inspiratory (Pint-I) intercostal interstitial pressures were 4 ± 0.5 and –2.8 ± 0.4 mmHg, respectively. Each of the above pressure values was obtained by averaging the corresponding pressure peaks in a time frame of up to 10 s.
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Ptm (bottom; Ptm = Plymph – Pint) is not constant from breath to breath but actually changes over time, shifting from –5.3 ± 0.5 mmHg at end expiration to 0.5 ± 0.3 mmHg at end inspiration.
In the attempt to verify whether two functionally different populations of lymphatic vessels could be distinguished on the basis of their absorptive (negative Ptm) or propulsive (positive Ptm) roles throughout the respiratory cycle, the end-inspiratory transmural pressure gradients (Ptm-I) were plotted as a function of the corresponding end-expiratory (Ptm-E) values, as shown in Fig. 3. Data points located in the quadrant 1 of Fig. 3 (n = 23, 57.5% of total data points) identify sites at which lymph may be formed during the entire respiratory cycle. Vice versa, data points in quadrant 3 (n = 6, 15% of total data points) correspond to lymphatic sites where Ptm favors propulsion only. However, 12.5% of the data points fell in quadrant 2 (n = 5), identifying vessels in which Ptm was negative during the end-expiratory pause and positive at end inspiration, whereas in another 15% of the vessels, Ptm was negative upon inspiration and positive during the end-expiratory phase (quadrant 4, n = 6). As a result of the dispersion of data points in the four quadrants, no significant linear regression (Ptm-I = –5.9 + 0.3Ptm-E; r2 = 0.05; n = 40) or correlation (correlation coefficient = 0.23; P = 0.15; n = 40) was found between the two variables. Hence, data suggest that a single lymphatic vessel may actually play an absorptive and/or a propulsive role, depending on the tissue stress acting on its wall during the respiratory cycle. Despite the great functional heterogeneity shown by data in Fig. 3, the Ptm averaged over the entire respiratory cycle was –7.6 ± 1.7 mmHg (n = 40) at the end-expiratory lung volume (Ptm-E) and did not significantly change at end inspiration (Ptm-I = –6. ± 1.4 mmHg).
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15 mmHg at end inspiration. Arterial and venous pressures averaged 95 ± 8.2 and 7.4 ± 2 mmHg, respectively, and were not significantly different from values previously observed during spontaneous breathing. During mechanical ventilation, Pesoph averaged –1.6 ± 0.7 mmHg at end expiration and increased to 2.8 ± 0.8 mmHg at end inspiration. An example of the Plymph and Pint traces during mechanical ventilation at positive alveolar pressure in paralyzed respiratory muscles is proposed in Fig. 2B. At variance with what was observed during spontaneous ventilation (Fig. 2A), Plymph and Pint both increased with increasing lung volume. In fact, on average, at end expiration with zero alveolar pressure, Plymph-E and corresponding Pint-E averaged –3.1 ± 1.2 (n = 7) and 2.6 ± 2.3 mmHg 8 (n = 7), respectively, and were not significantly different compared with the values attained during spontaneous breathing. However, at the end-inspiratory peak attained with positive alveolar pressure, Plymph-I and Pint-I significantly increased to 28.1 ± 7.8 (P < 0.001) and 28.2 ± 6.3 mmHg (P < 0.001), respectively, with an inspiratory tidal pressure change of 31.3 ± 8.5 and 25.6 ± 5.6 mmHg, respectively.
From the FFT analysis of the pressure signals (Fig. 4B), one may appreciate that although the major source of Plymph and Pint oscillations during mechanical ventilation is the respiratory component, this is not true for the Ptm, whose value at the ventilatory frequency (1 Hz) does not substantially differ from that of other components, including the cardiogenic one (3 Hz). In addition, at variance with what was observed during spontaneous breathing (Fig. 4A), when the inspiratory Ptm peak was much higher than the corresponding Plymph and Pint peaks, with mechanical ventilation the Ptm component was significantly reduced during inspiration.
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Ptm-E) and –0.1 ± 5.9 mmHg at end inspiration (Ptm-I). Over the entire respiratory cycle, Ptm was –1.1 ± 1.7 mmHg, not significantly different from zero and significantly lower (P = 0.005, one-way ANOVA) than the value observed in spontaneously breathing animals (Ptm = –6.8 ± 1.2 mmHg).
Cardiogenic oscillations.
The amplitude of the cardiogenic oscillations was very variable and determined, on average, a tidal increase of Plymph-E and Pint-E of 5.5 ± 2 (n = 21) and 5.1 ± 0.7 mmHg (n = 21), respectively. Such cardiogenic Plymph and Pint swings generated a Ptm amounting to –3.7 ± 1.61 mmHg, a value not significantly different from that observed across the wall of lymphatic vessels running on the pleural surface of the muscular part of the paralyzed rat diaphragm (14, 18). When performing a FFT analysis of a time frame of typical Plymph, Pint, and Ptm traces, it is possible to distinguish the prevalent component of pressure oscillation. For instance, Fig. 4A presents such an analysis performed on traces in Fig. 2A; one may appreciate that the respiratory component, at 1.5 Hz, is the most relevant source of Plymph and Pint pressure oscillation and, more significantly, of Ptm, whereas the cardiogenic component (at 3.2 Hz in this example) is distinguishable only in the Plymph recording. Note that the significant peak observed in Fig. 4A at 0.3 Hz is artifactual and is due to the slow drift observed in the Pint trace and thus calculated Ptm values (see Fig. 2A). Cardiogenic oscillations amounting to 2 mmHg also are visible in the Pint and Ptm traces in Fig. 2B, corresponding to the oscillation component at 3 Hz in Fig. 4B.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Methodological evaluation.
The micropuncture technique used in the present study offers the great advantage of allowing measurements of hydraulic pressure in tissues and in microvessels that would not be otherwise accessible. However, pressure measurement might be affected by artifacts caused by possible distortion of the flexible pipette tip and change in recording site within the moving tissue. To avoid tissue distortion during insertion, the pipette was driven into the tissue and/or the lymphatic vessel at an angle of 30° with respect to the tissue/vessel surface. This approach had been proven to be the least invasive during pipette insertion in steady intercostal interstitium (7). The similarity between present Plymph-E values and those obtained in paralyzed rabbits (14) and between present Pint-E values and those recorded in spontaneously breathing rats using saline-filled catheters (16) provides an indirect validation of this micropipette insertion approach in relatively still tissues.
Judging from the stereomicroscope images during recording, inspiratory chest expansion caused an outward and cranial displacement of the tissues of the order of 200–300 µm. In some instances, the deformation of the pipette tip against the vessel wall or the tissue fibers caused saturation of the pressure signal, leading to rejection of the reading. However, when the pipette was inserted along the major axis of the lymph vessel, or parallel to it in the interstitium, distortion was minimized and a stable and reproducible recording was obtained over several minutes. This insertion technique also allowed us to clearly distinguish whether the tip was in the vessel or in the adjacent interstitium. In any case, the completely opposite response observed in Plymph and Pint for similar tidal volume changes attained with active inspiration or passive lung inflation (Fig. 2, A and B) suggests that possible artifacts caused by the recording device might only marginally affect the actual values.
Plymph, Pint, and Ptm during the respiratory cycle in spontaneous and mechanical ventilation.
As observed in previous studies carried out using the same technique on paralyzed rabbits and rats, both the diaphragmatic (18) and the intercostal (14) lymphatic vessels of sizes ranging from 50 to 300 µm may be functionally regarded as initial lymphatics (22). In fact, the pressure oscillations caused by spontaneous contraction of the lymphatic smooth muscle cells, commonly observed in organs such as the mammalian mesentery or the bat wing (1, 22), were only very rarely encountered in the present and in our previous studies (14, 18). Hence, from this standpoint, pleural lymphatics seem to functionally behave like the lymphatics network supplying other tissues that undergo high tissue stresses, such as the skeletal muscle (23, 24) and the myocardium (5).
Pint-E depends on the local stress exerted between the solid macromolecular elements in the tissue as well as on the water content of the tissue (1) as indicated by the progressive increase of Pint with overhydration (9). Because intercostal microvasculature provides net fluid filtration into the tissue (15), the absorptive gradient required to maintain the interstitial fluid homeostasis, as well as the negative end-expiration Pint value, is therefore set by the lymphatic drainage, which indeed provides absorptive Ptm (Fig. 3, quadrants 1 and 4) in most vessels at end expiration.
Upon inspiration, variable mechanical stresses arise in the intercostal tissues, resulting from the simultaneous contribution of multiple mechanical factors: 1) the inspiratory contraction of the external intercostal muscles that run ventrally in the craniocaudal direction and likely exert uneven tangential stresses on the differently oriented parasternal or paracostal subpleural interstitial fibers; the contribution of the external intercostal muscles to lung inflation varies markedly in the rostrocaudal direction, with the inspiratory rib displacement much more relevant in the rostral interspaces compared with the caudal ones (2, 3); and 2) the inspiratory decrease in pleural liquid pressure (Pliq), which exerts a further inward pull, acting perpendicularly to the pleural surface. Such a local mechanical complexity results in an increased local tensile stress, as suggested by the decrease in Plymph and Pint observed during spontaneous inspiration. The similarity between Pint and Plymph inspiratory swings suggests that the stress arising in the tissue during inspiration was entirely transmitted to the lymphatic vessel lumen through the solid matrix components. Indeed, the initial lymphatics are delimited by a highly compliant endothelial wall (22), which is not expected to modify the stress exerted by the tissue fibers to the lymphatic lumen via the anchoring filaments. The variable delay observed between Pint and Plymph changes at the spontaneous inspiratory onset (Fig. 2A) is likely related to the viscoelastic properties of the matrix fibers though which mechanical transmission of tissue stress to the outer lymphatic wall takes place. Such a delay, usually not present in mechanical ventilation in paralyzed rats (Fig. 2B), may reflect both changes in tissue compliance during intercostal muscle contraction or relaxation and/or alternate muscle recruitment.
During spontaneous breathing, tissue stress magnitude seems to be more effective than respiratory frequency in determining Ptm changes. Indeed, although the Ptm developing during cardiogenic oscillations may support lymph function in the paralyzed diaphragm (18), the amplitude of Ptm induced by respiratory activity is much prevailing (Fig. 4).
From a fluid dynamics standpoint, a negative Ptm value across the lymphatic wall potentially drives an interstitial to lymphatic fluid flow, thus promoting lymph formation. It is worth noting that the initial lymphatic vessel may be compared, from the mechanical standpoint, to a nonelastic collapsible vessel (4); therefore, the tensile stress exerted by the tissue fibers on the outer surface prevents vessel collapse despite the occurrence of a negative transmural pressure. In the majority (70%) of the recordings (Fig. 3, quadrants 1 and 2) Ptm was in favor of lymph formation during the end-expiratory phase. Provided that lymph pressure waves caused by the intrinsic spontaneous contraction of the smooth muscles cells were not observed in the present study, the setting and maintenance of the end-expiratory Ptm likely depend on cardiogenic oscillations, similar to those observed in the lymphatic diaphragmatic network of paralyzed rats (18). In intercostal tissues, the cardiogenic swings depend on 1) displacement of lung parenchyma and pleural liquid during cardiac motion and 2) mechanical transmission of arterial pressure waves along the elastic walls of the internal mammarian and intercostal arteries.
Whereas 60% of the lymphatic vessels contributed to lymph formation during the entire respiratory cycle (Fig. 3, quadrant 1), in 40% of the vessels a positive Ptm developed, at least transiently, suggesting the occurrence of either forward fluid propulsion and/or backflow toward the interstitial space. The actual direction of the fluid flux between the interstitium and the lymphatic lumen cannot be detected with the techniques used in the present study, and thus we cannot exclude the existence of lymphatic to interstitial fluid backflow. However, unidirectional flaplike valves located in the lymphatic vessel wall (primary valves) have been recently described in the lymphatics supplying the skeletal muscles (6, 24) and the diaphragm (17). Given that these valves seem to hinder fluid backflow, a positive Ptm might reasonably be interpreted in terms of lymph propulsion between adjacent lymphangions rather than as an index of retrograde fluid flux.
In paralyzed rats mechanically ventilated at zero end-expiratory alveolar pressure, Pint-E, Plymph-E, and Ptm-E did not significantly differ compared with their values during spontaneous breathing, suggesting that end-expiratory muscle tone did not significantly affect, per se, the lymphatic function, which was guaranteed by the unaffected cardiogenic oscillations. However, at variance with spontaneous breathing, Pint-I and Plymph-I both increased with passive lung inflation as a result of compressive tissue stress due to increased alveolar pressure. In this condition, the average Ptm-I was essentially nullified. This finding indicates that tissue stress induced by the intercostal muscle contraction and not the change in chest wall volume is required to support lymphatic function, which in this condition may only rely on the unaffected but less efficient cardiogenic oscillations (Fig. 4B).
Pleural fluid drainage. In spontaneously breathing rats at approximately heart level, costal Pliq averages approximately –2 mmHg at end expiration and approximately –3 mmHg at end inspiration, respectively (11, 16). Assuming that the present Plymph values reflect Plymph within the stomata (19) facing the pleural space, a net pressure gradient varying between approximately –0.5 mmHg at end expiration and approximately –18 mmHg at end inspiration, respectively, would develop between the pleural fluid and the stomata lumen. Therefore, during spontaneous breathing, lymph formation might occur through the whole respiratory cycle, and in particular upon inspiration. Pleural fluid drainage would instead be hindered during mechanical ventilation when Plymph becomes positive.
In summary, the analysis of Ptm development during either the respiratory or cardiac cycle shows that the active contraction of inspiratory muscles and not the chest wall volume change is required to enhance lymph formation and progression in the thoracic lymphatics. The three-dimensional architecture of matrix macromolecules, their arrangement in the intercostal spaces, and their mechanical properties seem to play a fundamental role in determining and modulating lymph formation and propulsion in these initial lymphatics under spontaneous breathing. Given the importance of the lymphatic system in controlling fluid homeostasis in the thoracic tissues and in particular in the pleural cavity, mechanical ventilation per se is therefore expected to determine an increase of thoracic tissues hydration and pleural effusion. A similar situation may well occur in the lung parenchyma, motivating the latent subedematous condition often observed in lungs of patients exposed to positive pressure ventilatory regimes.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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