Impairment of transalveolar fluid transport  and lung Na<sup>+</sup>-K<sup>+</sup>-ATPase function by hypoxia in rats

Suzuki, Satoshi; Noda, Masafumi; Sugita, Makoto; Ono, Shigehiro; Koike, Kazuhiko; Fujimura, Shigefumi

doi:10.1152/jappl.1999.87.3.962

Cited by 57 publications

(39 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this hypothesis, inhibition of the Na-K-ATPase by ouabain decreases nasal PD in the rat [26]. Moreover, in mice, Na-K-ATPase activity represents a potential limiting step in respiratory transepithelial sodium transport [10], and, in the rat, hypoxia decreases nasal PD [26], alveolar fluid clearance and Na-K-ATPase function [27]. However, since ENaC and Na-K-ATPase work in series, one would expect that impairment of Na-K-ATPase function increases intracellular sodium and, in turn, results in a reduced gradient for Na z entry.…”

Section: Discussionmentioning

confidence: 69%

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Sartori¹,

Duplain²,

Lepori³

et al. 2004

Eur Respir J

View full text Add to dashboard Cite

High-altitude pulmonary oedema (HAPE) occurs in predisposed individuals at altitudes w2,500 m. Defective alveolar fluid clearance secondary to a constitutive impairment of the respiratory transepithelial sodium transport contributes to its pathogenesis. Hypoxia impairs the transepithelial sodium transport in alveolar epithelial type II cells in vitro. If this impairment is also present in vivo, high-altitude exposure could aggravate the constitutive defect in sodium transport in HAPE-prone subjects, and thereby further facilitate pulmonary oedema.Therefore, the aim of the current study was to measure the nasal potential difference (PD) in 21 HAPE-prone and 29 HAPE-resistant subjects at low altitude and 30 h after arrival at high altitude (4,559 m).High-altitude exposure significantly decreased the mean¡SD nasal PD in HAPEprone (18.0¡6.2 versus 12.5¡6.8 mV) but not in HAPE-resistant subjects (25.6¡9.4 versus 22.9¡9.2 mV). This altitude-induced decrease was not associated with an altered amiloride-sensitive fraction, but was associated with a significantly lower amilorideinsensitive fraction of the nasal PD.These findings provide evidence in vivo that an environmental factor may impair respiratory transepithelial sodium transport in humans. They are consistent with the concept that in high-altitude pulmonary oedema-susceptible subjects, the combination of a constitutive and an acquired defect in this transport mechanism facilitates the development of pulmonary oedema during high-altitude exposure. High-altitude pulmonary oedema (HAPE) is a lifethreatening condition that occurs in predisposed but otherwise healthy individuals at altitudes w2,500 m. Augmented alveolar fluid flooding related to exaggerated hypoxic pulmonary vasoconstriction plays an important role in its pathogenesis, secondary to endothelial dysfunction and sympathetic overactivity [1][2][3]. However, recent observations indicate that this mechanism may not be sufficient to cause high-altitude pulmonary oedema [4].Active sodium transport across the alveolar epithelium plays an important role in keeping the lungs free of fluid [5,6]. In alveolar epithelial cells, sodium enters the apical membrane primarily through the amiloride-sensitive cation channels (mainly ENaC), and is then transported across the basolateral membrane into the interstitium by the ouabain-inhibitable Na-K-ATPase [5][6][7][8].A genetic impairment of the transepithelial sodium transport mechanism facilitates pulmonary oedema in transgenic mice [9,10] and possibly also in humans, as suggested by HAPE-prone subjects who have a smaller nasal potential difference (PD) (an indirect marker of vectorial sodium transport in the distal airways) [11] than mountaineers resistant to this condition [12]. Consistent with this concept, prophylactic stimulation of this transport mechanism with the b 2 -adrenergic agonist salmeterol, at a dose that stimulates respiratory sodium transport in vitro [8] and increases alveolar fluid clearance in vivo [13], decreased the incidence of HAPE in h...

show abstract

Section: Discussionmentioning

confidence: 69%

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Sartori¹,

Duplain²,

Lepori³

et al. 2004

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…At variance with the systemic circulation, studies directly measuring endothelial function in the lung are limited to the invasive approach or to a simple, and in part questionable, correlation with a systemic endothelial flow-mediated response 40 . Nonetheless, there is a strong rationale for taking the gas diffusing properties across the alveoli as an indirect indicator of endothelial permeability and therefore endothelial activity 26 .…”

Section: Detection Of Lung Capillary Injury In Clinical Practice: Relmentioning

confidence: 99%

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

Guazzi¹,

Phillips²,

Arena³

et al. 2015

Progress in Cardiovascular Diseases

View full text Add to dashboard Cite

Cardiac dysfunction of both systolic and diastolic origin leads to increased left atrial pressure, lung capillary injury and increased resistance to gas transfer. Acutely, pressure-induced trauma disrupts the endothelial and alveolar anatomical configuration and definitively causes an impairment of cellular pathways involved in fluid-flux regulation and gas exchange efficiency, a process well identified as stress failure of the alveolarcapillary membrane. In chronic heart failure (HF), additional stimuli other than pressure may trigger the true remodeling process of capillaries and small arteries characterized by endothelial dysfunction, proliferation of myofibroblasts, fibrosis and extracellular matrix deposition. In parallel there is a loss of alveolar gas diffusion properties due to the increased path from air to blood (thickening of extracellular matrix) and loss of fine molecular mechanism involved in fluid reabsorption and clearance. Deleterious changes in gas transfer not only reflect the underlying lung tissue damage but also portend independent prognostic information and may play a role in the pathogenesis of exercise limitations and ventilatory abnormalities observed in these patients. Few currently approved treatments for chronic HF have the potential to positively affect structural remodeling of the lung capillary network; angiotensin-converting enzyme inhibitors are one of the few currently established options. Recently, more attention has been paid to novel therapies specifically targeting the nitric oxide pathway as a suitable target to improve endothelial function and permeability as well as alveolar gas exchange properties.

show abstract

“…2 Sodium enters the apical membrane of alveolar epithelial cells through amiloride-sensitive Na ϩ channels (2,3) and is then transported out across the basolateral membrane by the ouabain-inhibitable Na,K-ATPase (4 -7). Hypoxia has been shown to impair AFR and may contribute to alveolar fluid accumulation (8,9). However, the mechanisms by which hypoxia impairs AFR and alveolar epithelial sodium transport proteins has not been fully elucidated.…”

mentioning

confidence: 99%

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Litvan

Briva

Wilson

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Hypoxia has been shown to cause lung edema and impair lung edema clearance. In the present study, we exposed isolated rat lungs to pO 2 ‫؍‬ 40 mm Hg for 60 min or rats to 8% O 2 for up to 24 h and then measured changes in alveolar fluid reabsorption (AFR) and Na,K-ATPase function. Low levels of oxygen severely impaired AFR in both ex vivo and in vivo models. The decrease in AFR was associated with a decrease in Na,K-ATPase activity and protein abundance in the basolateral membranes from peripheral lung tissue of hypoxic rats. ␤-Adrenergic agonists restored AFR in rats exposed to 8% O 2 (from 0.02 ؎ 0.07 ml/h to 0.59 ؎ 0.03 ml/h), which was associated with parallel increases in Na,K-ATPase protein abundance in the basolateral membrane. Hypoxia is associated with increased production of reactive oxygen species. Therefore, we examined whether overexpression of SOD2, manganese superoxide dismutase, would prevent the hypoxia-mediated decrease in AFR. Spontaneously breathing rats were infected with a replication-deficient human type 5 adenovirus containing cDNA for SOD2. An otherwise identical virus that contained no cDNA was used as a control (Adnull). Hypoxic Adnull rats had decreased rates of AFR (0.12 ؎ 0.1 ml/h) as compared with hypoxic AdSOD2 and normoxic control rats (0.47 ؎ 0.04 ml/h and 0.49 ؎ 0.02 ml/h, respectively), with parallel changes in Na,K-ATPase.Severe hypoxia can occur during ascent to high altitude (1) and in patients with acute respiratory distress syndrome and pulmonary edema. One of the primary defense mechanisms in the lung against alveolar fluid accumulation is the active transport of sodium out of the air spaces, which generates a transepithelial osmotic gradient that leads to alveolar fluid reabsorption (AFR).2 Sodium enters the apical membrane of alveolar epithelial cells through amiloride-sensitive Na ϩ channels (2, 3) and is then transported out across the basolateral membrane by the ouabain-inhibitable Na,K-ATPase (4 -7). Hypoxia has been shown to impair AFR and may contribute to alveolar fluid accumulation (8, 9). However, the mechanisms by which hypoxia impairs AFR and alveolar epithelial sodium transport proteins has not been fully elucidated.A mechanism by which hypoxia might impair AFR is by altering the function of either apical epithelial sodium channels and/or basolateral Na,K-ATPase proteins. Several in vitro studies using cultured alveolar epithelial cells have demonstrated that exposure to hypoxia results in the decrease in epithelial sodium channels and Na,K-ATPase protein abundance (10 -12), which was reversed upon reoxygenation. Other investigators have reported various mechanisms associated with the decrease in alveolar fluid reabsorption in animals exposed to hypoxia in vivo (9,11,13).In the current study, we provide evidence that exposure to hypoxia results in decreased Na,K-ATPase activity and protein abundance at the plasma membrane, which contributes to a decrease in alveolar fluid reabsorption in both in vivo and ex vivo models of hypoxia. These data suggest that (a...

show abstract

Impairment of transalveolar fluid transport and lung Na⁺-K⁺-ATPase function by hypoxia in rats

Cited by 57 publications

References 32 publications

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Contact Info

Product

Resources

About

Impairment of transalveolar fluid transport and lung Na+-K+-ATPase function by hypoxia in rats

Cited by 57 publications

References 32 publications

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

β-Adrenergic Receptor Stimulation and Adenoviral Overexpression of Superoxide Dismutase Prevent the Hypoxia-mediated Decrease in Na,K-ATPase and Alveolar Fluid Reabsorption

Contact Info

Product

Resources

About

Impairment of transalveolar fluid transport and lung Na⁺-K⁺-ATPase function by hypoxia in rats