Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line

Planès, Carole; Friedlander, Gérard; Loiseau, Alain; Amiel, Catherine; Clérici, Christine

doi:10.1152/ajplung.1996.271.1.l70

Cited by 50 publications

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“…ATP homeostasis in hypoxia has been explained in many cases as resulting from inhibition of energy-consuming processes. In ATII cells, activity of the Na ϩ -K ϩ -ATPase in maintenance of fluid homeostasis may account for as much as 20% of cellular ATP demand, with prior work demonstrating suppression of this process in hypoxia (10,27). Hypoxic ATII cells undergo endocytosis and degradation of this plasma membrane-associated Na ϩ -K ϩ -ATPase, resulting in a large decrease in the necessity of the cell to produce ATP to maintain bioenergetic homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

Lottes

Newton

Spyropoulos

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lottes RG, Newton DA, Spyropoulos DD, Baatz JE. Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation. Am J Physiol Lung Cell Mol Physiol 306: L947-L955, 2014. First published March 28, 2014 doi:10.1152/ajplung.00298.2013.-Although many lung diseases are associated with hypoxia, alveolar type II epithelial (ATII) cell impairment, and pulmonary surfactant dysfunction, the effects of O 2 limitation on metabolic pathways necessary to maintain cellular energy in ATII cells have not been studied extensively. This report presents results of targeted assays aimed at identifying specific metabolic processes that contribute to energy homeostasis using primary ATII cells and a model ATII cell line, mouse lung epithelial 15 (MLE-15), cultured in normoxic and hypoxic conditions. MLEs cultured in normoxia demonstrated a robust O 2 consumption rate (OCR) coupled to ATP generation and limited extracellular lactate production, indicating reliance on oxidative phosphorylation for ATP production. Pharmacological uncoupling of respiration increased OCR in normoxic cultures to 175% of basal levels, indicating significant spare respiratory capacity. However, when exposed to hypoxia for 20 h, basal O2 consumption fell to 60% of normoxic rates, and cells maintained only ϳ50% of normoxic spare respiratory capacity, indicating suppression of mitochondrial function, although intracellular ATP levels remained at near normoxic levels. Moreover, while hypoxic exposure stimulated glycogen synthesis and storage in MLE-15, glycolytic rate (as measured by lactate generation) was not significantly increased in the cells, despite enhanced expression of several enzymes related to glycolysis. These results were largely recapitulated in murine primary ATII, demonstrating MLE-15 suitability for modeling ATII metabolism. The ability of ATII cells to maintain ATP levels in hypoxia without enhancing glycolysis suggests that these cells are exceptionally efficient at conserving ATP to maintain bioenergetic homeostasis under O 2 limitation. mitochondrial function; metabolism THE ALVEOLAR EPITHELIUM FORMS the barrier between the pulmonary vasculature and the external milieu and serves as the surface across which O 2 and waste gases are exchanged. Because of their physical location, the cells that line alveoli in developed human lungs are normally exposed to an exceptionally well-oxygenated environment of ϳ13% O 2 in nondiseased lungs (i.e., a PO 2 of ϳ105 mmHg compared with a PO 2 of ϳ40 mmHg in peripheral blood) (33). However, decreases in alveolar O 2 tensions (pulmonary hypoxia) can result from a number of pathological conditions, including chronic obstructive pulmonary disease, lung cancers, and pulmonary hypertension and edema (34). In contrast, differentiation and development of the fetal lung distal epithelium normally occurs in low O 2 (1-5% O 2 ) (19), with hypoxia-related signaling in the pulmonary epithelium throughout gestation (8,9,28). This condition is critical for normal fetal lung ...

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Section: Discussionmentioning

confidence: 99%

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

Lottes

Newton

Spyropoulos

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In alveolar epithelial type II cells, hypoxia decreases Na-K-ATPase mRNA expression and activity [15]. It has been suggested that alveolar epithelial type II cells exposed to hypoxia may release a soluble factor that inhibits Na-K-ATPase activity [28]. Interestingly, highaltitude exposure stimulates the release of an endogenous digoxin-like factor, which may have inhibitory effects on transepithelial sodium transport [29].…”

Section: Discussionmentioning

confidence: 99%

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

Sartori¹,

Duplain²,

Lepori³

et al. 2004

Eur Respir J

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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...

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“…This has been shown to occur in alveolar epithelial cells (Planès et al, 1996;Dada et al, 2003) via an HIF-1␣ independent mechanism , and is thought to contribute to pulmonary edema under hypoxic conditions. Our experiments have demonstrated that hypoxia mediated regulation of Na ϩ /K ϩ ATPase also occurs in DRG neurons also.…”

Section: Effects Of Endoneurial Hypoxia On the Namentioning

confidence: 99%

Peripheral Nerve Injury Induces Persistent Vascular Dysfunction and Endoneurial Hypoxia, Contributing to the Genesis of Neuropathic Pain

et al. 2015

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Nerve injury is associated with microvascular disturbance; however, the role of the vascular system has not been well characterized in the context of neuropathic pain. Furthermore, ischemia is thought to play a role in a number of neuropathic pain conditions, and yet the role of hypoxia has also not been characterized in neuropathic pain conditions. In this study, we observed the presence of persistent endoneurial hypoxia in a mouse model of traumatic peripheral nerve injury, causing painful mononeuropathy. We attribute the ongoing hypoxia to microvascular dysfunction, endoneurial fibrosis, and increased metabolic requirements within the injured nerve. Increased lactate levels were observed in injured nerves, as well as increased oxygen consumption and extracellular acidification rates, suggesting that anaerobic glycolysis is required to maintain cellular ATP levels. Hypoxia causes a reduction in levels of the Na ϩ /K ϩ ATPase ion transporter in both cultured primary dorsal root ganglion neurons and injured peripheral nerve. A reduction of Na ϩ /K ϩ ATPase ion transporter levels likely contributes to the hyperexcitability of injured nerves. Physiological antagonism of hypoxia with hyperbaric oxygen alleviated mechanical allodynia in nerve-injured animals. These results suggest that hypoxia and the Na ϩ /K ϩ ATPase ion transporter may be a novel mechanistic target for the treatment of neuropathic pain. In addition, the findings support the possibility of using hypoxia activated pro-drugs to localize treatments for neuropathic pain and nerve injury to injured nerves.

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Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line

Cited by 50 publications

References 0 publications

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation

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

Peripheral Nerve Injury Induces Persistent Vascular Dysfunction and Endoneurial Hypoxia, Contributing to the Genesis of Neuropathic Pain

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