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1 Department of Internal Medicine
2 the Botnar Center for Clinical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
3
Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
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Abstract |
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-subunit of the amiloride-sensitive sodium channel (ENaC(–/–)), impaired sodium transport-mediated lung liquid clearance at birth results in neonatal death. Transgenic expression of ENaC driven by a cytomegalovirus (CMV) promoter (ENaC(–/–)Tg+) rescues the lethal pulmonary phenotype, but only partially restores respiratory sodium transport in vitro. To test whether this may also be true in vivo, and to assess the functional consequences of this defect on experimental pulmonary oedema, we measured respiratory transepithelial potential difference (PD) and alveolar fluid clearance (AFC), and quantified pulmonary oedema during experimental acute lung injury in these mice. Both respiratory PD and AFC were roughly 50% lower (P < 0.01) in ENaC(–/–)Tg+ than in control mice. This impairment was associated with a significantly larger increase of the wet/dry lung weight ratio in ENaC(–/–)Tg+ than in control mice, both after exposure to hyperoxia and thiourea. Moreover, the rate of resolution of thiourea-induced pulmonary oedema was more than three times slower (P < 0.001) in ENaC(–/–)Tg+ mice. ENaC(–/–)Tg+ mice represent the first model of a constitutively impaired respiratory transepithelial sodium transport, and provide direct evidence that this impairment facilitates pulmonary oedema in conscious freely moving animals. These data in mice strengthen indirect evidence provided by clinical studies, suggesting that defective respiratory transepithelial sodium transport may also facilitate pulmonary oedema in humans.
(Received 19 April 2004;
accepted after revision 9 August 2004;
first published online 12 August 2004)
Corresponding author U. Scherrer: Department of Internal Medicine, BH 10.642, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. Email: urs.scherrer{at}hospvd.ch
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Introduction |
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-subunit of the amiloride-sensitive sodium channel (ENaC(–/–)) (Canessa et al. 1994) die within the first hours of life from failure to clear the fetal lung fluid (Hummler et al. 1996). However it is difficult to extrapolate observations made during the first hours of life to the adult period, as the perinatal transition is characterized by unique physiological changes in the lung, as reflected by AFC rates in newborn guinea pigs that are nearly two times faster than after maximal pharmacological stimulation in adult life (Finley et al. 1998).
Due to the lack of an adult in vivo model of defective respiratory sodium transport, the study of the specific contribution of this transport to the pathogenesis of pulmonary oedema was limited to measurements of exogenous fluid clearance in anaesthetized and ventilated animals, and in ex vivo animal preparations over short periods of time, during experimental interventions intended to stimulate or inhibit transepithelial sodium transport (Matthay et al. 1982; Pittet et al. 1994; Garat et al. 1997, 1998; Finley et al. 1998; Campbell et al. 1999; Charron et al. 1999; Folkesson et al. 2000; Hardiman et al. 2001). Introduction of a rat ENaC transgene under a heterologous CMV promoter into the ENaC knockout background (ENaC(–/–)Tg+) restores ENaC responsiveness to physiological and pharmacological stimuli in respiratory cells in vitro (Olivier et al. 2002), and rescues the lethal pulmonary phenotype (Hummler et al. 1997). ENaC(–/–)Tg+ mice develop normally. However, compared with the endogene, mRNA expression of the transgene is lower in the kidney, colon, and lung (Hummler et al. 1997; Olivier et al. 2002), and amiloride-sensitive sodium transport is impaired in tracheal explants in vitro (Olivier et al. 2002). We hypothesized that ENaC(–/–)Tg+ mice may represent an in vivo model of defective transepithelial respiratory sodium transport, and allow us to study its role in the pathogenesis of pulmonary oedema in adult life.
We therefore measured nasal and tracheal transepithelial potential difference (PD), an index of the electrogenic transport of Na+ and Cl– ions across the distal respiratory epithelium (Boucher et al. 1980; Knowles et al. 1982; Grubb et al. 1994; Kelley et al. 1997), and AFC in ENaC(–/–)Tg+ and control mice in vivo. We found that both PD and AFC were defective. To examine the functional consequences of this defect, we compared the severity and time course of thiourea- and hyperoxia-induced pulmonary oedema (Cunningham & Hurley, 1972; Mais & Bosin, 1984; Zuege et al. 1996; Song et al. 2000) in ENaC(–/–)Tg+ and control mice.
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Methods |
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The total number of mice used in this study (ENaC(–/–)Tg+ mice and ENaC(+/+)Tg- control littermates) was 172. Mice were matched for age (12–16 weeks), sex and weight in all the experimental groups. Generation of the transgenic mice on a NMRI genetic background and breeding were as previously described (Hummler et al. 1997). Animals were housed in standard cages and light conditions, and fed standard rodent chow and water ad libitum. The experiments were approved by the institutional reviewing board on animal experimentation.
Measurement of nasal and tracheal transepithelial PD. For the measurement of nasal PD, a modification of previously described techniques was used (Boucher et al. 1980; Grubb et al. 1994; Ghosal et al. 1996). Briefly, mice were anaesthetized (ketamine, 0.1 mg (g body weight)–1 and xylazine, 0.01 mg (g body weight)–1; I.P., supplemented with additional doses throughout the experiment if necessary, to maintain an adequate depth of anaesthesia, i.e lack of motor and heart rate response to tail and/or paw pinch), and placed on a heating table to keep their body temperature between 37°C and 38°C. A stretched PE-10 tubing filled with pre-warmed (37°C) Ringer solution was inserted into the nostril of the spontaneously breathing mouse. The intranasal recording bridge and a subcutaneous reference bridge (an agar/Ringer solution-filled sterile 21-gauge needle), were linked by matched electrodes (Dri-Ref 5, World Precision Instruments Inc. Sarasota, FL, USA) to a high impedance voltmeter (ISOMIL, World Precision Instruments Inc.). The recording site was located at a depth of 2 mm from the nares. Once in place, the recording bridge was stabilized, and a stable plateau value was obtained for at least 30 s. The recording site in each nostril was revisited twice, and nasal PD was expressed as the average of the four measurements obtained for each animal.
Tracheal PD was measured by placing the recording bridge into the proximal part of the trachea in mice undergoing mechanical ventilation for the measurement of AFC (see below).
Measurement of in vivo AFC. AFC was measured by standard gravimetric method in anaesthetized (as above), paralysed (pancuronium, 0.01 mg (g body weight)–1, I.P), tracheotomised, mechanically ventilated (Mouse Ventilator Model 687, Harvard Apparatus, Inc.) mice. After 15 min of a stable baseline period, mice were instilled with Ringer solution containing 5% bovine serum albumin (BSA; Sigma) supplemented with concentrated saline solution to make it isosmolar (320 mosm l–1) with mouse plasma (Ma et al. 1998). Pre-warmed (37.5°C) solution (8 µl g–1) was instilled via the endotracheal cannula into both lungs. An alveolar fluid sample was collected by aspiration 15 min after instillation. AFC was expressed as percentage of the instilled fluid volume absorbed after 15 min, calculated from the final-to-instilled total albumin concentration ratio (Garat et al. 1998; Charron et al. 1999; Fukuda et al. 2000; Folkesson et al. 2000).
Measurement of lung barrier permeability. To estimate the leak of a vascular tracer protein (125I-albumin, injected intravenously 1 h before the end of the experiments) into the extravascular compartments of the lung (lung interstitium and air spaces), the total extravascular [125I]albumin accumulation in alveolar liquid recovered from the air spaces and the lung homogenate was measured, and expressed as extravascular plasma equivalents (Rezaiguia et al. 1997).
Measurement of pulmonary oedema. As an index of lung oedema, the amount of extravascular lung water was calculated according to established techniques (Pittet et al. 1994, 2001; Zuege et al. 1996). Briefly, animals were anaesthetized, as described above, and killed by exsanguination, the lungs were removed and the wet weight was recorded. The lungs were then placed in an incubator at 80°C for 24 h, and the dry weight was recorded. For each animal, the wet/dry weight ratio was calculated. Lung homogenate supernatant haemoglobin content was measured to calculate bloodless lung wet/dry weight ratios.
Classical wet/dry weight ratios were used to study the time course of the resolution of thiourea-induced pulmonary oedema. Bloodless wet/dry lung weight ratios were used to compare pulmonary oedema in animals with hyperoxic or thiourea-induced lung injury in order to exclude confounding effects of alveolar haemorrhage during hyperoxia.
Lung histology. Mice were killed as described above. The trachea was cannulated and connected to a syringe before thoracotomy, in order to prevent lung collapse and to re-adjust the lung volume to the thorax volume before fixation. Lungs were fixed by sequential immersion in isosmolar 1.5% glutaraldehyde, osmium tetroxide and uranyl acetate. Blocks (1 mm3) were excised from the right middle lobe, embedded in Epon resin, cut in 1-µm thin sections and stained with toluidine blue for light microscopic examination (Bachofen et al. 1993).
Specific experimental protocols
Nasal and tracheal PD. Baseline measurements (n = 6 mice for each group) were performed before and after administration of drug-free water as vehicle aerosol (in order to control for non-specific effects of the aerosolization on nasal PD). The values after vehicle aerosol were used as baseline values. The aerosol was generated by a nebulizing system (Respirgard-II, Marquest Inc., Englewood, CO, USA) run at 8 l min–1 for 2 min, resulting in aerosolization of 1 ml min–1 of aerosol solution. Anaesthetized mice were breathing the aerosol through a custom-built open-flow face mask. Vehicle aerosol did not alter nasal PD. In the same animals we also measured the amiloride-sensitive fraction of nasal PD after a 2-min aerosolization of amiloride (10–3 M dissolved in water) (Ghosal et al. 1996; Tomlinson et al. 1999). Mice were allowed at least 48 h of recovery between the two measurements. Amiloride and vehicle were administered in random order.
The effects of mechanical ventilation on nasal PD and the relationship between nasal and tracheal PD were studied in mechanically ventilated mice prepared as described in the section on AFC, above (n = 5 mice for each group).
AFC under normal conditions.
Baseline AFC was quantified in ENaC(–/–)Tg+ and control mice (n = 6 for each group) by instillation of the 5% BSA solution prepared as described above.
To measure the amiloride-sensitive fraction of AFC in ENaC(–/–)Tg+ and control mice (n = 6 for each group), Amiloride (10–3 M) was added to the 5% BSA solution.
Thiourea-induced pulmonary oedema.
Thiourea causes acute lung oedema by increasing vascular permeability (Cunningham & Hurley, 1972). In normal mice, its effect peaks around 4 h after injection, and the time for resolution of the oedema is 
12 h (Mais & Bosin, 1984). Preliminary experiments revealed a dose–response relationship with a maximal effect at a dose of 40 mg kg–1 I.V. This dose was subsequently used.
Lungs were excised 4 h after intravenous injection of thiourea or saline for lung histology or measurement of the bloodless wet/dry lung weight ratio. To study the time course of lung oedema, classical wet/dry weight ratios were measured 3, 4, 5, 6 and 7 h (n = 4–6 mice per group at each time point) after thiourea injection. The rate of resolution of pulmonary oedema was expressed as percentage decrease per hour of the peak increase of the wet/dry lung weight ratio over baseline values. To quantify AFC during thiourea-mediated lung injury, ENaC(–/–)Tg+ and control mice (n = 5 for each group) were instilled with 5% BSA 4 h after thiourea administration (40 mg kg–1 i.v). In order to account for the initial dilution of the instillate by the presence of pulmonary oedema, we collected an additional alveolar fluid sample 1 min after instillation, and calculated AFC from the albumin concentration changes over the following 15 min in these groups (Hardiman et al. 2001).
Hyperoxia-induced pulmonary oedema. Hyperoxic lung injury was induced by exposing the mice to an inspired O2 fraction (Fi,O2) > 98% in a sealed Plexiglas chamber. Lung histology, bloodless wet/dry lung weight ratio and AFC were measured after 72 h of hyperoxia, using the techniques described in the previous sections.
All measurements and calculations were carried out by an investigator who was unaware of mouse genotype.
Statistical analysis
Data were analysed with the JMP software package (SAS Institute Inc.). Statistical analysis was performed with two-way ANOVA for between-group comparisons as a function of time, and with two-tailed paired or unpaired t tests for single comparisons. Relations between variables were analysed by calculating Pearson's product-moment correlation coefficient. Unless otherwise indicated, data are given as means ± S.D. A P-value below 0.05 was considered to indicate statistical significance.
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Results |
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Baseline nasal PD was almost 40% lower in ENaC(–/–)Tg+ than in control mice (12.2 ± 1.4 mV versus 20.0 ± 3.2 mV, P < 0.001, Fig. 1). Similarly, tracheal PD was significantly lower in ENaC(–/–)Tg+ than in control mice (8.3 ± 1.8 mV versus 13.1 ± 2.8 mV, P < 0.05). Amiloride induced a significant decrease of the nasal PD in both wild-type and transgenic mice. However, this decrease was more than five times smaller in the transgenic than in the control mice (1.8 ± 2.1 versus 10.1 ± 4.2 mV, P < 0.001). Residual nasal PDs after amiloride were comparable in the two groups (10.4 ± 1.6 mV versus 9.9 ± 1.4 mV, Fig. 1). Nasal PD was comparable in spontaneously breathing and mechanically ventilated mice, and in ventilated mice, nasal and tracheal PDs were closely correlated (r = 0.95, P < 0.001, Fig. 2).
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Consistent with the findings for nasal PD, baseline AFC was 55% lower in ENaC(–/–)Tg+ than in control mice (6.0 ± 1.9 versus 13.4 ± 1.9%, P < 0.001, Fig. 3). The amiloride-induced decrease of AFC in control mice (–69%, P < 0.001 versus baseline) was nearly three times larger than in ENaC(–/–)Tg+ mice (–24%, P = 0.36 versus baseline). The amiloride-insensitive fractions of AFC were comparable in the two groups (Fig. 3).
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At baseline, the macroscopic appearance of the lungs was normal in transgenic and control mice. The bloodless wet/dry lung weight ratios were similar in both groups (4.18 ± 0.33 versus 4.26 ± 0.56, P = 0.73, Fig. 5), and no alveolar fluid was detectable on histological examination (Fig. 7A and B), indicating that under normal conditions, defective AFC in ENaC(–/–)Tg+ mice was not associated with fluid accumulation in the lung. In contrast, after thiourea administration, the peak increase of the bloodless wet/dry weight ratio was significantly larger in the transgenic than in the control mice (5.87 ± 0.38 versus 4.82 ± 0.25, P < 0.01; Fig. 5), and the rate of resolution of pulmonary oedema was more than three times slower (6.9 versus 22.2% decrease of the wet/dry weight ratio per hour, P < 0.001, Fig. 6). Three hours after the peak increase, the wet/dry lung weight ratio had returned to near-baseline values in wild-type animals, whereas 80% of the excess water was still present in the lungs of the transgenic mice. Consistent with these findings, histological examination of the lung, harvested 4 h after thiourea administration, revealed alveolar oedema that was more marked in ENaC(–/–)Tg+ than in control mice (Fig. 7C and D).
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After hyperoxia, the differences between the two groups were even more pronounced than after thiourea. The increase in bloodless wet/dry weight ratio was nearly six times larger in ENaC(–/–)Tg+ than in control mice (from 4.3 ± 0.6 to 7.2 ± 1.2 versus from 4.2 ± 0.3 to 4.6 ± 0.6, respectively, P < 0.001; Fig. 5). ENaC(–/–)Tg+ mice showed more severe symptoms (lethargy and respiratory distress) of lung oedema; at the opening of the chest, their lungs appeared dark red and stiffened, whereas the lungs of control mice were only slightly discoloured. Histological examination of the lung revealed marked alveolar oedema with entire acini being fluid-filled and collapsed in ENaC(–/–)Tg+ mice, whereas alveolar oedema was barely detectable in control mice (Fig. 7E and F). Interstitial oedema appeared comparable in the two groups.
AFC and lung barrier permeability during experimental pulmonary oedema
AFC.
The difference of AFC between ENaC (–/–)Tg+ and control mice was maintained during experimental pulmonary oedema (thiourea: ENaC (–/–)Tg+, 5.7 ± 2.6; control, 15.7 ± 4.1%, P < 0.01; hyperoxia: ENaC(–/–)Tg+, 5.8 ± 2.6; control, 10.0 ± 0.9%, P < 0.01).
Lung barrier permeability (125I-albumin studies).
Baseline albumin flux out of the vascular space was comparable in ENaC(–/–)Tg+ and control mice (47.7 ± 6.0 and 41.8 ± 7.6 µl g–1 of lung tissue, respectively). Thiourea and hyperoxia significantly and comparably increased the lung vascular albumin leak in wild-type and transgenic mice (thiourea: 85.8 ± 2.8 and 98.7 ± 9.0 µl g–1 lung tissue, respectively; hyperoxia: 63.1 ± 11.5 and 77.1 ± 14.5 µl g–1 lung tissue, respectively), suggesting that differences in lung barrier permeability did not contribute to the augmented susceptibility to pulmonary oedema in the transgenic mice.
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Discussion |
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ENaC(–/–)Tg+ mice had a roughly 50% lower respiratory transepithelial PD and AFC compared to control mice. This constitutive impairment of the respiratory sodium transport had important pathophysiological consequences, as it augmented the severity and delayed the resolution of experimental pulmonary oedema in conscious, freely moving mice.
Transepithelial PD has been used extensively as an indirect bioelectric marker of in vivo respiratory sodium transport in mice (Grubb et al. 1994; Kelley et al. 1997) and humans (Boucher et al. 1980; Knowles et al. 1982; Kerem et al. 1999; Sartori et al. 2002). Here we show that nasal and tracheal PD were almost 50% smaller in ENaC(–/–)Tg+ mice than in wild-type littermates. Consistent with earlier data (Boucher et al. 1980; Knowles et al. 1982), the values measured in the upper and lower airways were closely correlated. The defect of the respiratory ion transport in ENaC(–/–)Tg+ mice was almost entirely related to its amiloride-sensitive component, as evidenced by residual PDs that were comparable after amiloride treatment in the two groups. The significantly smaller respiratory PD in ENaC(–/–)Tg+ mice was mirrored by a quantitatively similar impairment of AFC. The amiloride-sensitive fraction of the AFC almost entirely accounted for this impairment. Moreover, there was a close relationship between respiratory PD and AFC measurements. The latter observation represents the first direct demonstration that the respiratory PD is a marker of AFC in the more distal airways.
Taken together, these data indicate that respiratory transepithelial sodium transport and sodium transport-driven AFC are significantly impaired in ENaC(–/–)Tg+ mice, and that the amiloride-sensitive, ENaC-mediated component accounts for the main part of this impairment. These findings are in accordance with data showing decreased pulmonary mRNA levels of the transgene in ENaC(–/–)Tg+ mouse lungs (Hummler et al. 1997), a markedly lower amiloride-sensitive fraction of the transepithelial short-circuit current in primary cultures of tracheal cells from ENaC(–/–)Tg+ mice in vitro (Hummler et al. 1997), and an almost abolished amiloride-sensitive rectal PD in adult transgenic mice in vivo (Hummler et al. 1997). The insensitivity to amiloride in vivo, in the present and these earlier studies, is probably related to a low expression of the transgene rather than to defective regulation of ENaC, because tracheal explants from ENaC transgenic mice respond normally to pharmacological and environmental stimuli (Olivier et al. 2002).
The impairment of the respiratory sodium transport and AFC in ENaC(–/–)Tg+ mice had no pathophysiological consequences under normal conditions, as evidenced by the normal wet/dry lung weight ratio and lung histology in both groups. However, in the presence of augmented alveolar fluid flooding after exposure to hyperoxia or thiourea administration, ENaC(–/–)Tg+ mice showed an exaggerated increase of the wet/dry lung weight ratio and more severe pulmonary oedema on histological examination. This difference does not appear to be related to differences in blood pressure, sympathetic tone or propensity to develop heart failure between the two groups (data not shown). The more severe pulmonary oedema was related specifically to defective sodium transport-dependent fluid clearance, as the difference of AFC between the two groups persisted during experimental pulmonary oedema, whereas the alveolo-capillary barrier permeability in ENaC(–/–)Tg+ and control mice was comparable under all experimental conditions.
Earlier in vivo studies on the role of transepithelial sodium transport in the pathogenesis of pulmonary oedema were limited to the measurement of the clearance of exogenous liquid over short time periods, during experimental interventions intended to alter the transepithelial sodium transport in anaesthetized, paralysed and ventilated animals (Matthay et al. 1982; Pittet et al. 1994; Garat et al. 1997, 1998; Finley et al. 1998; Campbell et al. 1999; Charron et al. 1999; Folkesson et al. 2000; Hardiman et al. 2001). Here, ENaC(–/–)Tg+ mice allowed us, for the first time, to directly assess the functional consequences of an impaired respiratory transepithelial sodium transport on the time course of experimental pulmonary oedema over an extended time period of up to 72 h in conscious, freely moving mice in vivo.
A few studies in humans have addressed the potential importance of respiratory transepithelial sodium transport in fluid homeostasis of the lung. In premature infants, pulmonary oedema in respiratory distress syndrome is associated with a transient decrease of the nasal PD (Barker et al. 1997). In patients susceptible to high-altitude pulmonary oedema, nasal PD is lower than in mountaineers resistant to this condition (Sartori et al. 2004), and prophylactic stimulation of transepithelial sodium transport with a ß-adrenergic agonist prevented pulmonary oedema during high-altitude exposure in susceptible subjects (Sartori et al. 2002). The present demonstration of a close relationship between respiratory PD, AFC and susceptibility to experimental pulmonary oedema in mice, strengthens the indirect evidence provided by these clinical studies, and is consistent with the novel concept that defective respiratory transepithelial sodium transport may facilitate pulmonary oedema in humans (Fig. 8).
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Footnotes |
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M. R. Looney, C. Sartori, S. Chakraborty, P. F. James, J. B. Lingrel, and M. A. Matthay Decreased expression of both the {alpha}1- and {alpha}2-subunits of the Na-K-ATPase reduces maximal alveolar epithelial fluid clearance Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L104 - L110. [Abstract] [Full Text] [PDF]
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) and control mice (
). r = 0.95; P < 0.001.
