FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 346:1631-1636 May 23, 2002 Number 21 Next

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Voelkel, N. F. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models.

Methods In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition.

Results Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P<0.001).

Conclusions Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.

In mice, deletion of the subunit of the amiloride-sensitive epithelial sodium channel leads to neonatal death because of failure to clear the liquid from the lungs³; experimentally induced dysfunction of this channel impairs the clearance of alveolar fluid and predisposes mice to pulmonary edema.⁴ Beta-adrenergic agonists increase vectorial sodium transport in vitro,⁵ enhance the clearance of alveolar fluid in the resected human lung⁶ and in several species of animals,^7,8,9,10 and accelerate the resolution of pulmonary edema in animal models of lung injury.^{11,12,13,14,15} However, the effects of beta-adrenergic agonists in the treatment of pulmonary edema in humans have not been assessed, and information demonstrating the importance of this vectorial sodium transport in the development of and recovery from pulmonary edema in humans is sparse and indirect.^16,17

In a double-blind, placebo-controlled study, we tested whether the prophylactic inhalation of the beta-adrenergic agonist salmeterol at a dose shown to stimulate the clearance of alveolar fluid¹⁸ decreases the incidence of pulmonary edema during exposure to high altitudes in subjects who are prone to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference (a marker of the transepithelial sodium and water transport in the distal airways)^19,20,21,22 at low altitude in subjects who were prone to high-altitude pulmonary edema, subjects who were resistant to this condition, and subjects who had had transient perinatal pulmonary hypertension.

Methods

Study Subjects

Between June 1999 and July 2001, we studied 51 mountaineers who had had at least one radiographically documented episode of high-altitude pulmonary edema within the previous four years, 33 control subjects who had repeatedly engaged in alpine-style climbing to peaks higher than 4000 m with no symptoms of high-altitude pulmonary edema or acute mountain sickness, and 7 subjects with a history of transient perinatal pulmonary hypertension. The experimental protocols were approved by the institutional review board for human investigations at the Centre Hospitalier Universitaire Vaudois, and all subjects provided written informed consent.

Studies at High Altitude

Thirty-seven subjects who were prone to high-altitude pulmonary edema participated in the studies conducted at high altitude. One to four weeks after a base-line physical examination at an altitude of 580 m (barometric pressure, 710 mm Hg), the subjects ascended in less than 22 hours from 1130 m to 4559 m (barometric pressure, 440 mm Hg). The subjects were taken by cable car to an altitude of 3200 m; they then climbed for 1 1/2 hours to an altitude of 3611 m, where they stayed overnight; the next morning, they climbed for an additional 4 1/2 hours to the high-altitude research laboratory at Capanna Regina Margherita in Italy. The subjects then spent two days and two nights at this laboratory. On each of the two mornings, they were examined by the same observer, who used the Lake Louise acute-mountain-sickness scoring system (range of possible scores, 0 to 24, with higher scores indicating greater disease).²³

Thirty to 36 hours after each subject arrived, we estimated the systolic pulmonary-artery pressure (by echocardiography). On the morning before the descent, posteroanterior chest radiographs were obtained, and we measured the oxygen saturation of the hemoglobin (with a pulse oximeter attached to the fingertip) and the partial pressure of arterial oxygen and carbon dioxide (in samples of blood obtained from the radial artery). In subjects in whom clinical signs and symptoms of high-altitude pulmonary edema developed, chest radiographs and measurements of pulmonary-artery pressure and blood gases were obtained when the symptoms appeared, and the study was terminated and the subjects were treated and evacuated to low altitude.

Drug Administration

The subjects were instructed to use a pressurized metered-dose inhaler connected to a spacer (Volumatic, Glaxo Wellcome) and, after stratification according to the number of previous episodes of high-altitude pulmonary edema, were randomly assigned to inhale either 125 µg of salmeterol (Serevent, Glaxo Wellcome) or placebo every 12 hours. The administration started on the morning of the day before the subjects began the ascent to high altitude and was continued until the end of the study.

Echocardiography

To estimate systolic pulmonary-artery pressure, echocardiographic recordings were obtained with a real-time, phased-array sector scanner (model 5500, Hewlett–Packard) with an integrated color Doppler system and a transducer containing crystal sets for imaging (2.5 to 4.0 MHz) and for continuous-wave Doppler recording (1.9 MHz). The recordings were stored on SVHS videotape for analysis by an investigator who was unaware of the treatment-group assignments. All reported values represent the mean of at least three measurements.

Systolic pulmonary-artery pressure was calculated from the pressure gradient between the right ventricle and the right atrium, measured with continuous-wave Doppler echocardiography, and the clinically determined mean jugular venous pressure.²⁴ Color Doppler echocardiography was used to locate the tricuspid-regurgitation jet. The maximal velocity was then determined by careful application of the continuous-wave sampler on the regurgitation jet. To calculate the transtricuspid pressure gradient, a modified Bernoulli equation was used, in which transtricuspid pressure equaled four times the square of the peak tricuspid-jet velocity. Systolic pulmonary-artery pressure estimates obtained by echocardiography and measurements obtained by pulmonary-artery catheterization are closely correlated.²⁵

Radiography

Posteroanterior chest radiographs were obtained in all subjects with the use of a mobile unit (TRS, Siemens) with a fixed target-to-film distance of 140 cm at 133 kV and 4 to 6 mA per second. The radiographs were analyzed according to previously described criteria²⁴ by a radiologist who was unaware of the subject's clinical history. Briefly, with the mediastinum used as the vertical axis, and the hila as the horizontal axis, four areas of the lung were assessed separately for the presence of edema. The scoring system was as follows: normal parenchyma, 0; areas with questionable pathological findings, 1; sections of which less than 50 percent was affected by interstitial disease, 2; sections of which more than 50 percent was affected by nonconfluent interstitial disease, 3; areas of alveolar, partly confluent disease, 4. Any radiograph in which at least one quadrant of a lung had a score of 2 or higher was considered to be positive for high-altitude pulmonary edema.

Measurement of Transepithelial Sodium Transport at Low Altitude

A group of 33 mountaineers who were prone to high-altitude pulmonary edema (19 of whom had also participated in the high-altitude studies; 6 women and 27 men; mean [±SD] age, 36±8 years), the 33 control subjects (13 women and 20 men; mean age, 34±9 years), and the 7 subjects with a history of transient perinatal pulmonary hypertension (3 women and 4 men; mean age, 22±2 years) participated in this part of the study. The nasal transepithelial potential difference was measured with a recording bridge (polyethylene tubing filled with Ringer's solution) inserted under the inferior turbinate.^19,20 The intranasal recording bridge and a subcutaneous reference bridge (a sterile 21-gauge needle filled with agar and Ringer's solution) were linked by matched electrodes (Dri-Ref, World Precision Instruments) to a high-impedance voltmeter (Isomil, World Precision Instruments). During the measuring process, the recording bridge was perfused with isothermic (37°C) Ringer's solution (at a rate of 0.2 ml per minute). The difference in potential was measured at five distinct sites in each nostril by advancing or retracting the recording bridge by 0.5-cm intervals from the anterior to the posterior site, and vice versa. The potential difference was expressed in absolute values as the mean potential difference (the average of the five measurements obtained on each side). To determine the specific contribution of amiloride-sensitive sodium transport, we measured the effect of amiloride superfusion (floating amiloride over the nasal epithelium) on the nasal transepithelial potential difference at the site with the highest stable potential difference. Once a stable recording of potential difference had been obtained, amiloride (10^–4 mol per liter) was superfused at a rate of 5 ml per minute for three minutes through a second catheter.^19,20,21

Statistical Analysis

Statistical analyses were performed with JMP statistical software (SAS Institute) and involved paired or unpaired two-tailed t-tests for comparisons of single variables, as appropriate. Fisher's exact test was used to compare the effects of salmeterol on the incidence of pulmonary edema with those of placebo. Relations between variables were analyzed by calculating the Pearson product–moment correlation coefficients. A P value of less than 0.05 was considered to indicate statistical significance. Unless otherwise indicated, data are given as means ±SD.

Results

Studies at High Altitude

The characteristics of the 37 subjects studied at high altitude are shown in Table 1. Two subjects in the placebo group but none in the salmeterol group had spent time above 3000 m during the two months preceding the study. Eleven of the subjects in the placebo group and 14 of those in the salmeterol group had had more than one episode of high-altitude pulmonary edema. One subject in the placebo group and two in the salmeterol group reported tremor, nocturnal palpitations, or both. The mean heart rate was similar in the two groups.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the 37 Subjects Studied at High Altitude.

 
Prophylactic inhalation of salmeterol decreased the incidence of pulmonary edema; 14 of the 19 subjects in the placebo group (74 percent) but only 6 of the 18 subjects in the salmeterol group (33 percent) had clinical and radiographic evidence of pulmonary edema (P=0.02). Moreover, the mean radiographic score was more than 2.5 times as high in the placebo group as in the salmeterol group (P=0.006).

The subjects in the placebo group had more marked hypoxemia and more pronounced mountain sickness than those in the salmeterol group. There was an inverse correlation between the acute-mountain-sickness score and both the arterial oxygen saturation (r=–0.60, P<0.001) and the partial pressure of oxygen in the arterial blood (r=–0.66, P<0.001). Pulmonary-artery pressure did not differ significantly between the two groups.

Studies at Low Altitude

The nasal transepithelial potential-difference measurement was 32 percent lower among the subjects who were prone to high-altitude pulmonary edema (17.2±5.8 mV) than among the control subjects (25.4±9.6 mV) or the subjects with a history of transient perinatal pulmonary hypertension (27.8±9.7 mV, P<0.001 for both comparisons) (Figure 1). There was no significant difference between the sexes in the nasal transepithelial potential difference (data not shown). Amiloride superfusion caused a significantly smaller decrease in the nasal transepithelial potential difference in the subjects who were prone to high-altitude pulmonary edema (–10.0±4.6 mV) than in the control subjects (–15.3±7.3 mV) or the subjects with a history of transient perinatal pulmonary hypertension (–14.4±9.5 mV, P<0.001 for both comparisons). After amiloride superfusion, the nasal transepithelial potential difference in subjects who were prone to pulmonary edema (7.3±5.2 mV) was no longer significantly different from that in control subjects (10.1±6.8 mV).

View larger version (13K): [in this window] [in a new window]   Figure 1. Mean Base-Line Bioelectrical Indexes of Nasal Transepithelial Sodium Transport. Thirty-three subjects who were prone to high-altitude pulmonary edema, 33 control subjects who were not susceptible to high-altitude pulmonary edema, and 7 adult subjects with a history of transient perinatal pulmonary hypertension were studied. P<0.001 for the comparison between the subjects who were prone to high-altitude pulmonary edema and the control subjects. The I bars indicate the SE.

 
Discussion

We found that prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent. Several mechanisms could have contributed to this favorable effect. Enhancement of clearance of alveolar fluid may have played a part, since beta-adrenergic agonists up-regulate the clearance of alveolar fluid by stimulating transepithelial sodium transport²⁶ and attenuate alveolar flooding in animal models of lung injury (Figure 2).^{11,12,13,14,15} It is also possible that salmeterol, by improving alveolar ventilation and reducing alveolar hypoxia at high altitude, attenuates the hypoxia-induced impairment of alveolar absorption of sodium and fluid²⁷ in these subjects. Alternatively, salmeterol could act by protecting against the development of edema.

View larger version (60K): [in this window] [in a new window]   Figure 2. A Type II Alveolar Cell, Its Apical and Basal Sodium Channels, and the Possible Site of Action of Salmeterol. Sodium enters the apical membrane of alveolar cells mainly through amiloride-sensitive cation channels, such as the amiloride-sensitive epithelial sodium channel and the nonselective cation channel, and is then transported across the basolateral membrane into the interstitium by ouabain-inhibitable Na+/Ka+–ATPase. Salmeterol is thought to increase transepithelial sodium transport primarily by stimulating its amiloride-sensitive component and possibly by increasing the activity of Na+/Ka+–ATPase.

 
Prevention of pulmonary edema by the inhalation of salmeterol was not associated with an attenuation of altitude-induced pulmonary hypertension. This observation is consistent with the finding that the inhalation of salmeterol by sheep stimulates clearance of alveolar fluid without any detectable pulmonary hemodynamic effect.²⁸ It remains possible, however, that a hemodynamic action at the level of the pulmonary microcirculation, favorable effects on capillary permeability,²⁹ or both, may have contributed to the positive effect of salmeterol. Inhalation of salmeterol not only decreased the incidence of pulmonary edema, but also attenuated the symptoms of acute mountain sickness, an effect that appears to be related to the alleviation of hypoxemia.

The nasal transepithelial potential-difference value was 32 percent lower in the subjects who were prone to pulmonary edema than in the control subjects, suggesting a defect of transepithelial sodium and water transport that may be related, at least in part, to an impairment of its amiloride-sensitive fraction.^30,31 We speculate that this defect of transepithelial sodium transport may facilitate the development of pulmonary edema in humans. This hypothesis is consistent with the finding that such a transport defect predisposes mice to exaggerated accumulation of pulmonary fluid during acute lung injury,³² whereas a normal transport function appears to protect humans from pulmonary edema in the face of exaggerated altitude-induced pulmonary hypertension (as evidenced by the results of studies in the subjects with a history of transient perinatal pulmonary hypertension).

In summary, the present studies demonstrate the clinical benefit of an inhaled beta-adrenergic agonist for reducing pulmonary edema in humans. Moreover, the results suggest that a predisposition to high-altitude pulmonary edema may be associated with defective sodium-dependent clearance of alveolar fluid. We speculate that in other disease states associated with augmented alveolar flooding and hypoxia, such as heart failure and the acute respiratory distress syndrome, a preexisting defect of respiratory sodium transport may facilitate the development of pulmonary edema or, by delaying its resolution, increase the incidence of related illness and death. Beta-adrenergic stimulation of the clearance of alveolar fluid may represent a novel therapeutic strategy to prevent such potentially fatal outcomes.

Supported by grants from the Swiss National Science Foundation (grants 32.46797.96 and 3238-051157.97), the Placide Nicod Foundation, the Emma Muschamp Foundation, and the International Olympic Committee.

Presented in part at the 1998 Experimental Biology Meeting, San Francisco, April 18–23, 1998; the 11th International Hypoxia Symposium, Jasper, Alta., Canada, February 28–March 3, 1999; and the 96th International Conference of the American Thoracic Society, Toronto, May 5–10, 2000.

We are indebted to the participants; to the Sezione di Varallo del Club Alpino Italiano for providing the facilities at the Capanna Regina Margherita; to Mrs. Franziska Keller for taking the chest radiographs at high altitude; to Drs. Anton Nanzer and Marcel Schmid, Regionalspital Sta. Maria, Visp, for letting us study patients under their care; to Mrs. Käthy Heldner for help with the recruitment of the subjects; to Dr. Lionel Trueb for help with the studies at high altitude; to Dr. Domenico Lepori for reading the chest radiographs; to Dr. Peter Vollenweider for assistance with the manuscript; to Camille Anglada and Stéphane Gloor for technical assistance; to our mountain guides, Andrea Enzio and Bruno Brand; to Professor Erwin A. Koller for the use of his facilities; to Hewlett–Packard for providing the echocardiographic equipment; and to the Swiss Army for providing the radiographic equipment and transporting part of the material.

Source Information

From the Department of Internal Medicine (C.S., H.D., M.L., M.E., P.T., O.H., S.C., P.N., U.S.) and the Botnar Center for Clinical Research (C.S., H.D., M.L., M.E., P.T., O.H., S.C., U.S.), Centre Hospitalier Universitaire Vaudois, Lausanne; and the Swiss Cardiovascular Center, University Hospital, Bern (Y.A., E.L., D.H.) — both in Switzerland.

Address reprint requests to Dr. Scherrer at the Department of Internal Medicine, BH 10.642, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland, or at urs.scherrer{at}chuv.hospvd.ch.

References

1. Staub NC. Pulmonary edema. Physiol Rev 1974;54:678-811. [Free Full Text]
2. Matalon S, Benos DJ, Jackson RM. Biophysical and molecular properties of amiloride-inhibitable Na⁺ channels in alveolar epithelial cells. Am J Physiol 1996;271:L1-L22. [Medline]
3. Hummler E, Barker P, Gatzy J, et al. Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat Genet 1996;12:325-328. [CrossRef][Web of Science][Medline]
4. Egli M, Sartori C, Duplain H, et al. Impaired alveolar fluid clearance and augmented susceptibility to lung edema in mice with defective amiloride sensitive sodium transport. FASEB J 2000;14:A127-A127.abstract 
5. Suzuki S, Zuege D, Berthiaume Y. Sodium-independent modulation of Na(+)-K(+)-ATPase activity by beta-adrenergic agonist in alveolar type II cells. Am J Physiol 1995;268:L983-L990. [Medline]
6. Sakuma T, Okaniwa G, Nakada T, Nishimura T, Fujimura S, Matthay MA. Alveolar fluid clearance in the resected human lung. Am J Respir Crit Care Med 1994;150:305-310. [Abstract]
7. Crandall ED, Heming TA, Palombo RL, Goodman BE. Effects of terbutaline on sodium transport in isolated perfused rat lung. J Appl Physiol 1986;60:289-294. [Free Full Text]
8. Berthiaume Y, Staub NC, Matthay MA. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep. J Clin Invest 1987;79:335-343. [Web of Science][Medline]
9. Berthiaume Y, Broaddus VC, Gropper MA, Tanita T, Matthay MA. Alveolar liquid and protein clearance from normal dog lungs. J Appl Physiol 1988;65:585-593. [Free Full Text]
10. Garat CV, Carter EP, Matthay MA. New in situ mouse model to quantify alveolar epithelial fluid clearance. J Appl Physiol 1998;84:1763-1767. [Free Full Text]
11. Saldias FJ, Lecuona E, Comellas AP, Ridge KM, Rutschman DH, Sznajder JI. Beta-adrenergic stimulation restores rat lung ability to clear edema in ventilator-associated lung injury. Am J Respir Crit Care Med 2000;162:282-287. [Free Full Text]
12. Garat C, Meignan M, Matthay MA, Luo DF, Jayr C. Alveolar epithelial fluid clearance mechanisms are intact after moderate hyperoxic lung injury in rats. Chest 1997;111:1381-1388. [CrossRef][Web of Science][Medline]
13. Lasnier JM, Wangensteen OD, Schmitz LS, Gross CR, Ingbar DH. Terbutaline stimulates alveolar fluid resorption in hyperoxic lung injury. J Appl Physiol 1996;81:1723-1729. [Free Full Text]
14. Campbell AR, Folkesson HG, Berthiaume Y, Gutkowska J, Suzuki S, Matthay MA. Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep. J Appl Physiol 1999;86:139-151. [Free Full Text]
15. Vivona ML, Matthay M, Chabaud MB, Friedlander G, Clerici C. Hypoxia reduces alveolar epithelial sodium and fluid transport in rats: reversal by beta-adrenergic agonist treatment. Am J Respir Cell Mol Biol 2001;25:554-561. [Free Full Text]
16. Barker PM, Gowen CW, Lawson EE, Knowles MR. Decreased sodium ion absorption across nasal epithelium of very premature infants with respiratory distress syndrome. J Pediatr 1997;130:373-377. [CrossRef][Web of Science][Medline]
17. Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am Rev Respir Dis 1990;142:1250-1257. [Web of Science][Medline]
18. Atabai K, Ware LB, Snider M, et al. Aerosolized beta-2 agonists achieve therapeutic levels in the pulmonary edema fluid of ventilated patients. Am J Respir Crit Care Med 2001;163:Suppl:A618-A618.abstract 
19. Knowles M, Gatzy J, Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 1981;305:1489-1495. [Abstract]
20. Knowles MR, Carson JL, Collier AM, Gatzy JT, Boucher RC. Measurements of nasal transepithelial electric potential differences in normal human subjects in vivo. Am Rev Respir Dis 1981;124:484-490. [Web of Science][Medline]
21. Hofmann T, Bohmer O, Huls G, et al. Conventional and modified nasal potential-difference measurement in cystic fibrosis. Am J Respir Crit Care Med 1997;155:1908-1913. [Abstract]
22. Kerem E, Bistritzer T, Hanukoglu A, et al. Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med 1999;341:156-162. [Free Full Text]
23. Roach RC, Bärtsch P, Hackett PH, Oelz O, Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Houston CS, Coates G, eds. Hypoxia and molecular medicine. Burlington, Vt.: Charles S. Houston, 1993:272-4.
24. Scherrer U, Vollenweider L, Delabays A, et al. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 1996;334:624-629. [Free Full Text]
25. Allemann Y, Sartori C, Lepori M, et al. Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude. Am J Physiol Heart Circ Physiol 2000;279:H2013-H2016. [Free Full Text]
26. Matthay MA, Flori HR, Conner ER, Ware LB. Alveolar epithelial fluid transport: basic mechanisms and clinical relevance. Proc Assoc Am Physicians 1998;110:496-505. [Web of Science][Medline]
27. Tomlinson LA, Carpenter TC, Baker EH, Bridges JB, Weil JV. Hypoxia reduces airway epithelial sodium transport in rats. Am J Physiol 1999;277:L881-L886. [Web of Science][Medline]
28. Frank JA, Wang Y, Osorio O, Matthay MA. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol 2000;89:1255-1265. [Free Full Text]
29. Whelan CJ, Johnson M. Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea-pig lung and skin. Br J Pharmacol 1992;105:831-838. [Medline]
30. Canessa CM, Schild L, Buell G, et al. Amiloride-sensitive epithelial Na⁺ channel is made of three homologous subunits. Nature 1994;367:463-467. [CrossRef][Medline]
31. Matalon S, O'Brodovich H. Sodium channels in alveolar epithelial cells: molecular characterization, biophysical properties, and physiological significance. Annu Rev Physiol 1999;61:627-661. [CrossRef][Web of Science][Medline]
32. Lepori M, Hummler E, Feihl F, et al. Amiloride sensitive sodium transport dysfunction augments susceptibility to hypoxia-induced lung edema. FASEB J 1998;12:A39-A39.abstract 

Abstract PDF PDA Full Text PowerPoint Slide Set Perspective by Voelkel, N. F. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

Related Letters:

Salmeterol for the Prevention of High-Altitude Pulmonary Edema
Cruden N. L.M., Newby D. E., Webb D. J., Bärtsch P., Mairbäurl H., Basnyat B., Prodhan P., Noviski N. N., Kinane T. B., Swenson E. R., Maggiorini M., Scherrer U., Sartori C., Allemann Y.
Extract | Full Text | PDF  
N Engl J Med 2002; 347:1282-1285, Oct 17, 2002. Correspondence

This article has been cited by other articles:

• Zhang, S. X. L., Miller, J. J., Stolz, D. B., Serpero, L. D., Zhao, W., Gozal, D., Wang, Y. (2009). Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung. Am. J. Respir. Cell Mol. Bio. 40: 332-339 [Abstract] [Full Text]  
• Aksenov, I., Strauss, M. (2009). Diseases Related to High Altitude and Diving and Near-Drowning: Basics of Hyperbaric Medicine. ACCP Pulmonary Med Brd Rev 25: 729-740 [Full Text]  
• Luks, A. M., Johnson, R. J., Swenson, E. R. (2008). Chronic Kidney Disease at High Altitude. J. Am. Soc. Nephrol. 19: 2262-2271 [Abstract] [Full Text]  
• Stuber, T., Sartori, C., Salmon, C. S., Hutter, D., Thalmann, S., Turini, P., Jayet, P.-Y., Schwab, M., Sartori-Cucchia, C., Villena, M., Scherrer, U., Allemann, Y. (2008). Respiratory Nitric Oxide and Pulmonary Artery Pressure in Children of Aymara and European Ancestry at High Altitude. Chest 134: 996-1000 [Abstract] [Full Text]  
• Wolk, K. E., Lazarowski, E. R., Traylor, Z. P., Yu, E. N. Z., Jewell, N. A., Durbin, R. K., Durbin, J. E., Davis, I. C. (2008). Influenza A Virus Inhibits Alveolar Fluid Clearance in BALB/c Mice. Am. J. Respir. Crit. Care Med. 178: 969-976 [Abstract] [Full Text]  
• Schoene, R. B. (2008). Illnesses at High Altitude. Chest 134: 402-416 [Abstract] [Full Text]  
• Zhou, G., Dada, L. A., Sznajder, J. I. (2008). Regulation of alveolar epithelial function by hypoxia. Eur Respir J 31: 1107-1113 [Abstract] [Full Text]  
• Matthay, M. A., Calfee, C. S. (2008). Aerosolized {beta}-Adrenergic Agonist Therapy Reduces Pulmonary Edema Following Lung Surgery. Chest 133: 833-835 [Full Text]  
• Luks, A. M., Swenson, E. R. (2008). Medication and Dosage Considerations in the Prophylaxis and Treatment of High-Altitude Illness. Chest 133: 744-755 [Abstract] [Full Text]  
• Mutlu, G. M., Factor, P. (2008). Alveolar Epithelial 2-Adrenergic Receptors. Am. J. Respir. Cell Mol. Bio. 38: 127-134 [Abstract] [Full Text]  
• Bartsch, P., Gibbs, J. S. R. (2007). Effect of Altitude on the Heart and the Lungs. Circulation 116: 2191-2202 [Full Text]  
• Guney, S., Schuler, A., Ott, A., Hoschele, S., Zugel, S., Baloglu, E., Bartsch, P., Mairbaurl, H. (2007). Dexamethasone prevents transport inhibition by hypoxia in rat lung and alveolar epithelial cells by stimulating activity and expression of Na+-K+-ATPase and epithelial Na+ channels. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L1332-L1338 [Abstract] [Full Text]  
• Agostoni, P., Contini, M., Cattadori, G., Apostolo, A., Sciomer, S., Bussotti, M., Palermo, P., Fiorentini, C. (2007). Lung function with carvedilol and bisoprolol in chronic heart failure: Is {beta} selectivity relevant?. Eur J Heart Fail 9: 827-833 [Abstract] [Full Text]  
• Davis, I. C., Xu, A., Gao, Z., Hickman-Davis, J. M., Factor, P., Sullender, W. M., Matalon, S. (2007). Respiratory syncytial virus induces insensitivity to beta-adrenergic agonists in mouse lung epithelium in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L281-L289 [Abstract] [Full Text]  
• Snyder, E. M., Beck, K. C., Turner, S. T., Hoffman, E. A., Joyner, M. J., Johnson, B. D. (2007). Genetic variation of the beta2-adrenergic receptor is associated with differences in lung fluid accumulation in humans. J. Appl. Physiol. 102: 2172-2178 [Abstract] [Full Text]  
• Luks, A. M., Swenson, E. R. (2007). Travel to high altitude with pre-existing lung disease. Eur Respir J 29: 770-792 [Abstract] [Full Text]  
• Spooner, L. M., Olin, J. L., Debellis, R. J. (2007). Pharmacotherapy of High-Altitude Illness. AMERICAN JOURNAL OF LIFESTYLE MEDICINE 1: 129-141 [Abstract]  
• Calfee, C. S., Matthay, M. A. (2007). Nonventilatory Treatments for Acute Lung Injury and ARDS. Chest 131: 913-920 [Abstract] [Full Text]  
• Allemann, Y., Hutter, D., Lipp, E., Sartori, C., Duplain, H., Egli, M., Cook, S., Scherrer, U., Seiler, C. (2006). Patent Foramen Ovale and High-Altitude Pulmonary Edema. JAMA 296: 2954-2958 [Abstract] [Full Text]  
• Snyder, E. M., Beck, K. C., Hulsebus, M. L., Breen, J. F., Hoffman, E. A., Johnson, B. D. (2006). Short-term hypoxic exposure at rest and during exercise reduces lung water in healthy humans. J. Appl. Physiol. 101: 1623-1632 [Abstract] [Full Text]  
• Maggiorini, M., Brunner-La Rocca, H.-P., Peth, S., Fischler, M., Bohm, T., Bernheim, A., Kiencke, S., Bloch, K. E., Dehnert, C., Naeije, R., Lehmann, T., Bartsch, P., Mairbaurl, H. (2006). Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.. ANN INTERN MED 145: 497-506 [Abstract] [Full Text]  
• Swenson, E. R. (2006). Hypoxic lung whiteout: further clearing but more questions from on high.. ANN INTERN MED 145: 550-552 [Full Text]  
• Maggiorini, M. (2006). High altitude-induced pulmonary oedema. Cardiovasc Res 72: 41-50 [Abstract] [Full Text]  
• Litvan, J., Briva, A., Wilson, M. S., Budinger, G. R. S., Sznajder, J. I., Ridge, K. M. (2006). beta-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption. J. Biol. Chem. 281: 19892-19898 [Abstract] [Full Text]  
• Comellas, A. P., Dada, L. A., Lecuona, E., Pesce, L. M., Chandel, N. S., Quesada, N., Budinger, G. R. S., Strous, G. J., Ciechanover, A., Sznajder, J. I. (2006). Hypoxia-Mediated Degradation of Na,K-ATPase via Mitochondrial Reactive Oxygen Species and the Ubiquitin-Conjugating System. Circ. Res. 98: 1314-1322 [Abstract] [Full Text]  
• Cepkova, M., Matthay, M. A. (2006). Pharmacotherapy of Acute Lung Injury and the Acute Respiratory Distress Syndrome. J Intensive Care Med 21: 119-143 [Abstract]  
• Dehler, M., Zessin, E., Bartsch, P., Mairbaurl, H. (2006). Hypoxia causes permeability oedema in the constant-pressure perfused rat lung.. Eur Respir J 27: 600-606 [Abstract] [Full Text]  
• Matthay, M. A., Abraham, E. (2006). beta-Adrenergic Agonist Therapy as a Potential Treatment for Acute Lung Injury. Am. J. Respir. Crit. Care Med. 173: 254-255 [Full Text]  
• Perkins, G. D., McAuley, D. F., Thickett, D. R., Gao, F. (2006). The beta-Agonist Lung Injury Trial (BALTI): A Randomized Placebo-controlled Clinical Trial. Am. J. Respir. Crit. Care Med. 173: 281-287 [Abstract] [Full Text]  
• Jain, M., Sznajder, J. I. (2005). Effects of Hypoxia on the Alveolar Epithelium. Proc Am Thorac Soc 2: 202-205 [Abstract] [Full Text]  
• Matthay, M. A., Robriquet, L., Fang, X. (2005). Alveolar Epithelium: Role in Lung Fluid Balance and Acute Lung Injury. Proc Am Thorac Soc 2: 206-213 [Abstract] [Full Text]  
• West, J. B. (2005). The Physiologic Basis of High-Altitude Diseases. ANN INTERN MED 142: 592-592 [Full Text]  
• Pandit, A. (2005). The Physiologic Basis of High-Altitude Diseases. ANN INTERN MED 142: 591-591 [Full Text]  
• Bartsch, P., Mairbaurl, H., Maggiorini, M., Swenson, E. R. (2005). Physiological aspects of high-altitude pulmonary edema. J. Appl. Physiol. 98: 1101-1110 [Abstract] [Full Text]  
• Sartori, C., Egli, M., Scherrer, U. (2005). From the authors. Eur Respir J 25: 395-396 [Full Text]  
• Mutlu, G. M., Koch, W. J., Factor, P. (2004). Alveolar Epithelial {beta}2-Adrenergic Receptors: Their Role in Regulation of Alveolar Active Sodium Transport. Am. J. Respir. Crit. Care Med. 170: 1270-1275 [Full Text]  
• Mehta, D., Bhattacharya, J., Matthay, M. A., Malik, A. B. (2004). Integrated control of lung fluid balance. Am. J. Physiol. Lung Cell. Mol. Physiol. 287: L1081-L1090 [Abstract] [Full Text]  
• West, J. B. (2004). The Physiologic Basis of High-Altitude Diseases. ANN INTERN MED 141: 789-800 [Full Text]  
• Egli, M., Duplain, H., Lepori, M., Cook, S., Nicod, P., Hummler, E., Sartori, C., Scherrer, U. (2004). Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J. Physiol. 560: 857-865 [Abstract] [Full Text]  
• Thomas, C. P., Campbell, J. R., Wright, P. J., Husted, R. F. (2004). cAMP-stimulated Na+ transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1. Am. J. Physiol. Lung Cell. Mol. Physiol. 287: L843-L851 [Abstract] [Full Text]  
• Sartori, C., Duplain, H., Lepori, M., Egli, M., Maggiorini, M., Nicod, P., Scherrer, U. (2004). High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects. Eur Respir J 23: 916-920 [Abstract] [Full Text]  
• Liebler, J. M., Borok, Z., Li, X., Zhou, B., Sandoval, A. J., Kim, K.-J., Crandall, E. D. (2004). Alveolar Epithelial Type I Cells Express {beta}2-Adrenergic Receptors and G-protein Receptor Kinase 2. J. Histochem. Cytochem. 52: 759-767 [Abstract] [Full Text]  
• Sakuma, T., Zhao, Y., Sugita, M., Sagawa, M., Toga, H., Ishibashi, T., Nishio, M., Matthay, M. A. (2004). Malnutrition impairs alveolar fluid clearance in rat lungs. Am. J. Physiol. Lung Cell. Mol. Physiol. 286: L1268-L1274 [Abstract] [Full Text]  
• Maggiorini, M., Leon-Velarde, F. (2003). High-altitude pulmonary hypertension: a pathophysiological entity to different diseases. Eur Respir J 22: 1019-1025 [Abstract] [Full Text]  
• Mairbaurl, H., Schwobel, F., Hoschele, S., Maggiorini, M., Gibbs, S., Swenson, E. R., Bartsch, P. (2003). Altered ion transporter expression in bronchial epithelium in mountaineers with high-altitude pulmonary edema. J. Appl. Physiol. 95: 1843-1850 [Abstract] [Full Text]  
• Fiorenzano, G., Dottorini, M., Gabry, A. L., Martin, C. (2003). High-Altitude Pulmonary Edema. Chest 124: 1620-1621 [Full Text]  
• Berthiaume, Y. (2003). Long-term stimulation of alveolar epithelial cells by {beta}-adrenergic agonists: increased Na+ transport and modulation of cell growth?. Am. J. Physiol. Lung Cell. Mol. Physiol. 285: L798-L801 [Full Text]  
• Boyle, M. P., Diener-West, M., Milgram, L., Knowles, M., Foy, C., Zeitlin, P., Standaert, T. (2003). A Multicenter Study of the Effect of Solution Temperature on Nasal Potential Difference Measurements. Chest 124: 482-489 [Abstract] [Full Text]  
• Mason, N. P., Petersen, M., Melot, C., Imanow, B., Matveykine, O., Gautier, M.-T., Sarybaev, A., Aldashev, A., Mirrakhimov, M. M., Brown, B. H., Leathard, A. D., Naeije, R. (2003). Serial changes in nasal potential difference and lung electrical impedance tomography at high altitude. J. Appl. Physiol. 94: 2043-2050 [Abstract] [Full Text]  
• Barry, P W, Pollard, A J (2003). Altitude illness. BMJ 326: 915-919 [Full Text]  
• Hoschele, S., Mairbaurl, H. (2003). Alveolar Flooding at High Altitude: Failure of Reabsorption?. Physiology 18: 55-59 [Abstract] [Full Text]  
• Wooltorton, E. (2003). Salmeterol (Serevent) asthma trial halted early. CMAJ 168: 738-738 [Full Text]  
• Mairbaurl, H., Weymann, J., Mohrlein, A., Swenson, E. R., Maggiorini, M., Gibbs, J. S. R., Bartsch, P. (2003). Nasal Epithelium Potential Difference at High Altitude (4,559 m): Evidence for Secretion. Am. J. Respir. Crit. Care Med. 167: 862-867 [Abstract] [Full Text]  
• Ellsworth, A. (2003). Pharmacotherapy for Altitude-Related Illness. Journal of Pharmacy Practice 16: 68-75 [Abstract]  
• Raymond, L. W. (2003). Altitude Pulmonary Edema Below 8,000 Feet: What Are We Missing?. Chest 123: 5-7 [Full Text]  
• Carpenter, T. C., Schomberg, S., Nichols, C., Stenmark, K. R., Weil, J. V. (2003). Hypoxia reversibly inhibits epithelial sodium transport but does not inhibit lung ENaC or Na-K-ATPase expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 284: L77-L83 [Abstract] [Full Text]  
• Planes, C., Blot-Chabaud, M., Matthay, M. A., Couette, S., Uchida, T., Clerici, C. (2002). Hypoxia and beta 2-Agonists Regulate Cell Surface Expression of the Epithelial Sodium Channel in Native Alveolar Epithelial Cells. J. Biol. Chem. 277: 47318-47324 [Abstract] [Full Text]  
• Sartori, C., Matthay, M.A. (2002). Alveolar epithelial fluid transport in acute lung injury: new insights. Eur Respir J 20: 1299-1313 [Abstract] [Full Text]  
• Ware, L. B., Fang, X., Wang, Y., Sakuma, T., Hall, T. S., Matthay, M. A. (2002). Lung Edema Clearance: 20 Years of Progress: Selected Contribution: Mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung. J. Appl. Physiol. 93: 1869-1874 [Abstract] [Full Text]  
• Sartori, C., Fang, X., McGraw, D. W., Koch, P., Snider, M. E., Folkesson, H. G., Matthay, M. A. (2002). Lung Edema Clearance: 20 Years of Progress: Selected Contribution: Long-term effects of beta 2-adrenergic receptor stimulation on alveolar fluid clearance in mice. J. Appl. Physiol. 93: 1875-1880 [Abstract] [Full Text]  
• Olivier, R., Scherrer, U., Horisberger, J.-D., Rossier, B. C., Hummler, E. (2002). Lung Edema Clearance: 20 Years of Progress: Selected Contribution: Limiting Na+ transport rate in airway epithelia from alpha -ENaC transgenic mice: a model for pulmonary edema. J. Appl. Physiol. 93: 1881-1887 [Abstract] [Full Text]  
• Cruden, N. L.M., Newby, D. E., Webb, D. J., Bartsch, P., Mairbaurl, H., Basnyat, B., Prodhan, P., Noviski, N. N., Kinane, T. B., Swenson, E. R., Maggiorini, M., Scherrer, U., Sartori, C., Allemann, Y. (2002). Salmeterol for the Prevention of High-Altitude Pulmonary Edema. NEJM 347: 1282-1285 [Full Text]  
• Chinet, T. (2002). At the heart of pulmonary oedema. J. Physiol. 544: 335-335 [Full Text]  
• (2002). Preventing High-Altitude Pulmonary Edema with a Beta-Agonist. Journal Watch Cardiology 2002: 4-4 [Full Text]  
• Malik, I. (2002). JournalScan. Heart 88: 207-208 [Full Text]