Active sodium transport and alveolar epithelial Na-K-ATPase increase during subacute hyperoxia in rats

Active Na+ transport and lung edema clearance were studied in a model of lung injury caused by sublethal oxygen exposure. Rats exposed to 85% O2 for 7 days were studied at 0, 7, 14, and 30 days after removal from the hyperoxic chamber and compared with room air controls. In the isolated-perfused, fluid-filled rat lung, albumin flux from the perfusate into the air spaces increased after oxygen exposure and returned to control values after 7 days of recovery. However, permeability to small solutes (Na+ and mannitol) normalized only after 30 days of recovery from hyperoxia. Active Na+ transport increased immediately after oxygen exposure and returned to control values 7 days after removal from hyperoxic chamber. Na-K-adenosinetriphosphatase (ATPase) activity, and protein expression in alveolar epithelial type II cells obtained at the end of the isolated lung experiments increased significantly after the oxygen exposure compared with controls in association with the increased active Na+ transport. We conclude that active Na+ transport and lung liquid clearance are increased in the subacute hyperoxic phase of lung injury in rats, due in part to the upregulation of alveolar epithelial Na-K-ATPases. Conceivably, this behavior protects against the effects of lung injury by allowing the injured lung to clear edema more effectively. Accordingly, this upregulation may be targeted as a strategy to diminish edema in patients with lung injury.

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Isoproterenol improves ability of lung to clear edema in rats exposed to hyperoxia

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.1.30 ◽

1999 ◽

Vol 87 (1) ◽

pp. 30-35 ◽

Cited By ~ 65

Author(s):

F. J. Saldías ◽

A. Comellas ◽

K. M. Ridge ◽

E. Lecuona ◽

J. I. Sznajder

Keyword(s):

Lung Injury ◽

Alveolar Epithelium ◽

Lung Edema ◽

Active Sodium ◽

Adult Rats ◽

Alveolar Epithelial ◽

Rat Lungs ◽

Hyperoxic Lung Injury ◽

Normal Rat ◽

Stimulation Of

Exposure of adult rats to 100% O2 results in lung injury and decreases active sodium transport and lung edema clearance. It has been reported that β-adrenergic agonists increase lung edema clearance in normal rat lungs by upregulating alveolar epithelial Na+-K+-ATPase function. This study was designed to examine whether isoproterenol (Iso) affects lung edema clearance in rats exposed to 100% O2 for 64 h. Active Na+ transport and lung edema clearance decreased by ∼44% in rats exposed to acute hyperoxia. Iso (10−6 M) increased the ability of the lung to clear edema in room-air-breathing rats (from 0.50 ± 0.02 to 0.99 ± 0.05 ml/h) and in rats exposed to 100% O2 (from 0.28 ± 0.03 to 0.86 ± 0.09 ml/h; P < 0.001). Disruption of intracellular microtubular transport of ion-transporting proteins by colchicine (0.25 mg/100 g body wt) inhibited the stimulatory effects of Iso in hyperoxia-injured rat lungs, whereas the isomer β-lumicolchicine, which does not affect microtubular transport, did not inhibit active Na+ transport stimulated by Iso. Accordingly, Iso restored the lung’s ability to clear edema after hyperoxic lung injury, probably by stimulation of the recruitment of ion-transporting proteins (Na+-K+-ATPase) from intracellular pools to the plasma membrane in rat alveolar epithelium.

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Overexpression of the Na-K-ATPase α2-subunit improves lung liquid clearance during ventilation-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00076.2007 ◽

2008 ◽

Vol 294 (6) ◽

pp. L1233-L1237 ◽

Cited By ~ 17

Author(s):

Yochai Adir ◽

Lynn C. Welch ◽

Vidas Dumasius ◽

Phillip Factor ◽

Jacob I. Sznajder ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Basolateral Membrane ◽

Alveolar Epithelium ◽

Alveolar Epithelial ◽

Rat Lungs ◽

Injured Lung ◽

Normal Rat ◽

Lung Liquid ◽

Ventilation Induced Lung Injury

Mechanical ventilation with high tidal volumes (HVT) impairs lung liquid clearance (LLC) and downregulates alveolar epithelial Na-K-ATPase. We have previously reported that the Na-K-ATPase α2-subunit contributes to LLC in normal rat lungs. Here we tested whether overexpression of Na-K-ATPase α2-subunit in the alveolar epithelium would increase clearance in a HVT model of lung injury. We infected rat lungs with a replication-incompetent adenovirus that expresses Na-K-ATPase α2-subunit gene (Adα2) 7 days before HVT mechanical ventilation. HVT ventilation decreased LLC by ∼50% in untreated, sham, and Adnull-infected rats. Overexpression of Na-K-ATPase α2-subunit prevented the decrease in clearance caused by HVT and was associated with significant increases in Na-K-ATPase α2 protein abundance and activity in peripheral lung basolateral membrane fractions. Ouabain at 10−5 M, a concentration that inhibits the α2 but not the Na-K-ATPase α1, decreased LLC in Adα2-infected rats to the same level as sham and Adnull-infected lungs, suggesting that the increased clearance in Adα2 lungs was due to Na-K-ATPase α2 expression and activity. In summary, we provide evidence that augmentation of the Na-K-ATPase α2-subunit, via gene transfer, may accelerate LLC in the injured lung.

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Type I interferon promotes alveolar epithelial type II cell survival during pulmonary Streptococcus pneumoniae infection and sterile lung injury in mice

European Journal of Immunology ◽

10.1002/eji.201546201 ◽

2016 ◽

Vol 46 (9) ◽

pp. 2175-2186 ◽

Cited By ~ 10

Author(s):

Barbara B. Maier ◽

Anastasiya Hladik ◽

Karin Lakovits ◽

Ana Korosec ◽

Rui Martins ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Lung Injury ◽

Cell Survival ◽

Type I Interferon ◽

Type I ◽

Type Ii ◽

Alveolar Epithelial ◽

Type Ii Cell

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Aging impairs alveolar epithelial type II cell function in acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00093.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. L755-L769 ◽

Cited By ~ 1

Author(s):

Tolga Yazicioglu ◽

Christian Mühlfeld ◽

Chiara Autilio ◽

Cheng-Kai Huang ◽

Christian Bär ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Function ◽

Lung Injury ◽

Cell Senescence ◽

Proliferation Rate ◽

Type Ii ◽

Alveolar Epithelial ◽

Surfactant Activity ◽

Old Mice ◽

Young Mice

Morbidity and mortality rates in acute lung injury (ALI) increase with age. As alveolar epithelial type II cells (AE2) are crucial for lung function and repair, we hypothesized that aging promotes senescence in AE2 and contributes to the severity and impaired regeneration in ALI. ALI was induced with 2.5 μg lipopolysaccharide/g body weight in young (3 mo) and old (18 mo) mice that were euthanized 24 h, 72 h, and 10 days later. Lung function, pulmonary surfactant activity, stereology, cell senescence, and single-cell RNA sequencing analyses were performed to investigate AE2 function in aging and ALI. In old mice, surfactant activity was severely impaired. A 60% mortality rate and lung function decline were observed in old, but not in young, mice with ALI. AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised, and AE2 of old mice showed signs of cell senescence, increased inflammatory signaling, and impaired surfactant metabolism in ALI. These findings provide evidence that ALI promotes a limited proliferation rate, increased inflammatory response, and surfactant dysfunction in old, but not in young, mice, supporting an impaired regenerative capacity and reduced survival rate in ALI with advancing age.

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