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Published ahead of print on August 28, 2003, doi:10.1164/rccm.200207-702OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 1445-1448, (2003)
© 2003 American Thoracic Society

Na,K-ATPase Gene Transfer Increases Liquid Clearance during Ventilation-induced Lung Injury

Yochai Adir, Phillip Factor, Vidas Dumasius, Karen M. Ridge and Jacob I. Sznajder

Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, and Evanston Northwestern Healthcare, Evanston, Illinois

Correspondence and requests for reprints should be addressed to Jacob I. Sznajder, M.D., Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, 303 East Chicago, Tarry 14-707, Chicago, IL 60611. E-mail: j-sznajder{at}northwestern.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mechanical ventilation with high tidal volumes (HVT) downregulates alveolar Na,K-ATPase function and impairs lung liquid clearance. We hypothesized that overexpression of Na,K-ATPase in the alveolar epithelium could counterbalance these changes and increase clearance in a rat model of mild ventilation-induced lung injury. We used a surfactant-based system to deliver 4 x 109 plaque-forming units of E1a-/E3- recombinant adenovirus containing either a rat ß1 Na,K-ATPase subunit cDNA (adß1) or no cDNA (adnull) to rat lungs 7 days before ventilation with a VT of approximately 40 ml/kg (peak airway pressure of less than 35 cm H2O) for 40 minutes. Lung liquid clearance and Na, K-ATPase activity and protein abundance were increased in HVT adß1-infected lungs as compared with sham and adnull-infected HVT lungs. These results suggest that Na,K-ATPase subunit gene overexpression in the alveolar epithelium increases Na,K-ATPase function and lung liquid clearance in a model of HVT. We provide here the first evidence that using a genetic approach improves active Na+ transport and thus liquid clearance in the setting of mild ventilation-induced lung injury.

Key Words: gene therapy • ventilation-induced lung injury • Na,K-ATPase

High tidal volume (HVT) ventilation of rat lungs causes pulmonary edema (1–7) caused partly by alveolocapillary stress failure, stretch-pore phenomenon, surfactant dysfunction, and release of chemokines (1, 3, 8–14). Alveolar Na,K-ATPase is a key element in the epithelial active Na+ transport that keeps the airspaces free of excess fluid (1, 12, 15–17). A recent report demonstrated that ventilation of rat lungs with HVT (VT of approximately 40 ml/kg) inhibited lung liquid clearance (1). These findings were associated with decreased Na,K-ATPase activity in alveolar epithelial cells, suggesting that HVT mechanical ventilation downregulated pathways needed to preserve a dry alveolar airspace.

Na,K-ATPase function and lung liquid clearance can be pharmacologically upregulated in normal and injured lungs with ß-adrenergic agonists, dopamine, aldosterone, kertinocyte growth factor, and epidermal growth factor (8, 18–22). It has been shown that adenoviral-mediated gene transfer can result in overexpression of Na,K-ATPase in the alveolar epithelium and upregulate lung liquid clearance in normal and injured lungs (12, 15–17). Accordingly, we hypothesized that Na,K-ATPase overexpression in the alveolar epithelium could increase lung liquid clearance during HVT in rats. To test this hypothesis, we infected rat lungs with a replication-incompetent adenovirus to overexpress the rat Na,K-ATPase ß1 subunit gene before HVT mechanical ventilation and measured lung liquid clearance in an isolated perfused rat lung model.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Adenovirus Delivery
The use of animals for this study was approved by the Northwestern University Institutional Animal Care and Use Committee. Animals were handled according to National Institutes of Health guidelines. All animals were provided food and water ad libitum and were maintained on a 12-hour light–dark cycle. Replication-incompetent (E1a-/E3-) human type 5 adenoviruses containing expression cassettes with a human immediate/early CMV promoter/enhancer and a rat Na,K-ATPase ß1 subunit cDNA (adß1) or no cDNA (adnull) were constructed, propagated, purified, and titered as previously described (15). Adenoviruses (4 x 109 plaque-forming units/rat) were delivered to the lungs of adult, male Sprague-Dawley rats (275–300 g) using a 50% surfactant vehicle as previously described (12, 15, 16, 23). Rats were allowed to recover for 7 days before study to allow vector-induced host responses to subside. Viruses used in this study were from single preparations that were free of endotoxin (Endosafe; Charles River Laboratory, Wilmington, MA) and were without signs of replication competent adenovirus (to the maximum nontoxic dilution of 109 in A549 cells) or the adenoviral E1a gene (by polymerase chain reaction).

HVT Mechanical Ventilation
Rats were anesthetized with pentobarbital (50 mg/kg, intraperitoneally), tracheotomized, and ventilated for 40 minutes with a VT of 40 ml/kg (maximum peak airway pressures of less than 35 cm H2O) and a respiratory rate of 55 breaths per minute and compared with nonventilated control subjects.

Measurement of Lung Liquid Clearance
The isolated, fluid-filled, perfused lung preparation was performed immediately after HVT ventilation as previously described (1, 12, 15–17, 24). Changes in concentration of Evan's blue tagged-albumin instilled into the airspace were used to estimate the volume of fluid cleared from the alveolar airspace. The total unidirectional flux of Na+ from the alveolar space (i.e., active transport and passive movement) was calculated from the rate of loss of 22Na+ from the airspaces. Active Na+ transport was measured by fluid clearance, and passive Na+ flux was calculated from the concentration change of 22Na+ in the instillate and by subtracting the active Na+ flux (calculated from the rate of fluid clearance) from total Na+ flux (24). Similarly, the flux of mannitol was calculated from the rate of loss of 3H-mannitol from the airspaces (24). Albumin flux from the pulmonary circulation into the alveolar space was determined from the fraction of fluorescein isothiocyanate-labeled albumin, placed in the perfusate that appeared in the alveolar instillate during the experimental protocol.

Experimental Protocols
Six experimental groups of rats were used in this study: nonventilated/noninfected (n = 11), adß1 infected-nonventilated (n = 3), noninfected + HVT (n = 6), adß1 infected + HVT (n = 9), adnull + HVT (n = 7), and sham + HVT (n = 7). Three animals per group were treated with ouabain (5 x 10-4 M) placed in the vascular perfusate during clearance measurements.

Western Blot Analysis
Basolateral membrane (BLM) proteins were isolated from approximately 1 g of peripheral lung tissue (i.e., the distal 1–2 mm) from sham, adnull, and adß1-infected lungs of control and HVT and separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis as previously described (23). Immunodetection was achieved using a rabbit polyclonal anti-rat ß1 Na,K-ATPase antibody (Dr. Martin Vasallo, Spain) or monoclonal anti-rat {alpha}1 (Upstate Biotech Inc., Upsala, NY) primary antibody and a chemiluminescent detection system. The density of the bands was quantified and normalized to sham-infected control subjects.

Na,K-ATPase Function in BLMs
Twenty micrograms of BLM protein were resuspended in a high [Na+]/low [K+] reaction buffer as previously described (23). Na,K-ATPase activity was determined by measuring ATP hydrolysis in the presence and absence of 2.5 mM of ouabain. Results are expressed as nmol inorganic phosphate (Pi)/mg protein/hour.

Statistical Analysis
Data are presented as mean values ± SD or SEM. One-way analysis of variance was used when multiple comparisons were made. Differences among groups were considered significant when p was less than 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Lung Liquid Clearance
As shown in Figure 1 , HVT inhibited lung liquid clearance by approximately 50% in noninfected control (0.25 ± 0.4 ml/hour), sham (0.33 ± 0.04 ml/hour), and adnull (0.30 ± 0.01 ml/hour) rats as compared with nonventilated/noninfected control subjects (0.51 ± 0.03 ml/hour). Conversely, lung liquid clearance in adß1 lungs ventilated with HVT increased by approximately threefold as compared with the other HVT groups.



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  		Figure 1. Lung liquid clearance in isolated rat lungs was increased in high tidal volume (HVT) rat ß1 Na,K-ATPase subunit cDNA (adß1) lungs as compared with high tidal volume (HVT) lungs from uninfected (control [CT]), no cDNA (adnull), and sham-infected rat lungs. Ouabain (5 x 10-4 M, black bars) inhibited the adß1-increased clearance to a greater degree as compared with other control groups. Data represent mean ± SEM. *p < 0.0001 HVT adß1 (without ouabain, gray bars) versus all other ventilated groups, and p = 0.0327 HVT adß1 (without ouabain) versus nonventilated adß1; **p < 0.001 HVT control (without ouabain) versus nonventilated control.

 
The Na,K-ATPase inhibitor ouabain (5 x 10-4 M) decreased lung liquid clearance by approximately 50% in noninfected control, adnull, and sham-infected HVT rats as compared with nonventilated/noninfected control rats (Figure 1). Ouabain decreased lung liquid clearance to a greater degree in adß1-infected/HVT lungs than in the other groups, suggesting that the increase of lung liquid clearance in animal infected with adß1 was due to upregulation of the Na,K-ATPase.

Alveolar barrier function in this model was assessed by measuring the flux of three differently sized molecules (fluorescein isothiocyanate-albumin 22Na+ and 3H-mannitol). Permeability to 22Na+, 3H-mannitol and albumin was increased in HVT control, sham, and adnull lungs as compared with noninfected, nonventilated control subjects (Figure 2) . The epithelial lining fluid volume estimated by Evan's blue dye-tagged albumin dilution in the first BAL was increased in the noninfected or null-infected HVT lungs as compared with nonventilated control subjects (0.04 ± 0.003 vs. 0.01 ± 0.005 ml). In contrast, epithelial lining fluid in the HVT-adß1–treated lungs was not different than nonventilated/noninfected or infected lungs.



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  		Figure 2. Alveolar barrier permeability to solutes was assessed by measuring the flux of 22Na+ (black bars), 3H-mannitol (white bars) (A), and fluorescein isothiocyanate-albumin (B) between the airspace and vascular compartments of isolated rat lungs. Data represent mean ± SEM. CT = noninfected control subjects. (A) *p < 0.05 nonventilated control subjects versus HVT control sham and adnull. (B) *p < 0.05 versus nonventilated, noninfected control subjects.

 
Na,K-ATPase Protein Abundance
Cell membrane fractions enriched for the basolateral cell membrane (BLM) domain were prepared from peripheral lung tissue after HVT (Figure 3A) . Western blot analysis of BLMs from three animals per group demonstrated that adß1-infected lungs had increased Na,K-ATPase ß1 protein abundance as compared with HVT sham and adnull-infected lungs. Similarly, levels of the {alpha}1 subunit were increased in the adß1 lungs, suggesting that ß1 subunit overexpression is associated with recruitment of {alpha}1 subunits from intracellular pools to the cell BLMs.



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  		Figure 3. (A) Composite graph and a representative Western blot for Na,K-ATPase ß1 subunit and {alpha}1 subunit protein (10 µg/lane) abundance at the basolateral membranes isolated from peripheral rat lungs with HVT for 40 minutes. Data are mean ± SD, normalized to sham infected (n = 3). *p < 0.01 adß1 versus other groups. Closed bars = ß1 subunit; open bars = {alpha}1 subunit. (B) Na,K-ATPase activity (ouabain-sensitive ATP hydrolysis) at the basolateral membranes isolated from the peripheral lung of rats ventilated with HVT for 40 minutes. Data represent mean ± SEM. *p < 0.05, adß1 versus all other groups (n = 3). No differences were noted between nonventilated, noninfected control subjects and HVT sham or adnull lungs.

 
Na,K-ATPase Activity in Peripheral Lung BLMs
As shown on Figure 3 the ouabain-sensitive ATP hydrolysis (Na,K-ATPase activity) in BLMs isolated from the peripheral lung was increased in adß1-infected lungs as compared with sham and adnull-infected control subjects.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The pathophysiology of ventilation-induced lung injury includes changes of the alveolar–capillary barrier function, which results in leakage of fluid and blood constituents into the lung interstitium and alveolar airspaces (1–5, 9–12). Recent studies indicate that HVT ventilation decreased lung liquid clearance, increased alveolar epithelial permeability for small solutes, and decreased Na,K-ATPase activity (1). The decrease of active Na+ transport combined with increased alveolar barrier permeability results in edema accumulation (1, 8). These data suggest a paradigm in which the pulmonary edema observed during ventilation-induced lung injury can also be contributed by the impairment of alveolar fluid clearance.

In this study, we used an adenoviral-mediated gene transfer strategy that has been shown capable of overexpressing the Na,K-ATPase in the alveolar epithelium of rats (12, 15–17). Using this approach, we observed that increasing Na,K-ATPase expression and function (Figure 3) in lungs exposed to HVT increased lung liquid clearance up to approximately 300% as compared with other HVT lungs (Figure 1). HVT ventilation of rats decreased lung liquid clearance by approximately 50% and increased alveolar permeability in noninfected control subjects and adnull-infected lungs, confirming that this model causes injury and impairment in alveolar active Na+ transport in rats. As compared with previous studies (12, 15), the permeability for 22Na+, 3H-mannitol in nonventilated adß1-infected lungs was somewhat lower probably because of the use of more purified virus construction.

Western blot analysis of BLMs isolated from the peripheral lung of HVT rats demonstrated that ß1 subunit gene transfer increased the abundance of both the {alpha}1 and ß1 Na,K-ATPase subunits (Figure 3A). In parallel with these data, we observed that in adß1 rat lungs, there was a significant increase in Na,K-ATPase activity at the BLM fractions isolated from the peripheral lung (Figure 3B). These data are similar to a recent report from a different model of acute lung injury (16) and provide further support, albeit indirect, for the hypothesis that the ß1 subunit is rate limiting in the rat alveolar epithelial cells and that ß1 overexpression may cause recruitment of {alpha}1 subunits from intracellular pools to the plasma membrane (12, 16), although decreased degradation of the {alpha} subunit could also account for these results. ß1 subunit overexpression in this model of ventilation-induced lung injury had a greater effect on lung liquid clearance than in a model of hydrostatic pulmonary edema caused by increased left atrial pressure (16). The reasons for these differences have not yet been elucidated and warrant further study.

We have reported that ß-adrenergic agonists and dopamine improve lung liquid clearance in this model of ventilation-induced lung injury by causing (short-term) recruitment of Na,K-ATPase from intracellular pools to the plasma membrane of the alveolar epithelium (8). However, data from alveolar (25) and bronchial epithelial (26) cells as well as rat lungs (27) suggest that ß-receptors are subject to agonist-induced desensitization. As such, catecholamines may offer transient improvement in edema clearance, and gene therapy may offer a more prolonged treatment modality. However, a significant limitation of using the adenovirus vector is the variable inflammatory response that it causes in the lungs that required approximately 7 days for the lungs to heal. The combination of evolving adenovector technology that allows for prolonged transgene expression with fewer host responses (28) and recent data showing that adenovectors are capable of efficient gene transfer to severely injured, edematous rat lungs (29) suggest that gene transfer may become an additional tool for treatment of acute lung injury. This study represents the first genetic method to improve alveolar epithelial fluid clearance in a model of ventilation-induced lung injury.


   Acknowledgments
 
The authors thank Dr. David Rutschman for his help with this article.


   FOOTNOTES
 
Supported by the HL-48129, the Evanston Northwestern Healthcare Research Institute, and HL-66211.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: Y.A. has no declared conflict of interest; P.F. holds a patent for the use of Na,K-ATPase gene therapy for pulmonary edema and is an equity partner in a small biotechnology company developing such therapies for human use, no funds or other support for the research in this project were provided by this entity; V.D. has no declared conflict of interest; K.M.R. has no declared conflict of interest; J.I.S. gave a lecture in November 2002 at the Margaux conference on Critical Care, sponsored by Lilly, and received an honorarium which was donated to fellowship research fund; his family purchased shares (less than 100) of Glaxo and Amgen.

Received in original form July 15, 2002; accepted in final form August 24, 2003


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
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