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

2008 ◽  
Vol 294 (6) ◽  
pp. L1233-L1237 ◽  
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.

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

1999 ◽  
Vol 87 (1) ◽  
pp. 30-35 ◽  
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.

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

1994 ◽  
Vol 266 (5) ◽  
pp. L577-L584 ◽  
Author(s):  
W. Olivera ◽  
K. Ridge ◽  
L. D. Wood ◽  
J. I. Sznajder
Keyword(s):  
Lung Injury ◽  
Lung Edema ◽  
Type Ii ◽  
Active Sodium ◽  
Na Transport ◽  
Alveolar Epithelial ◽  
Oxygen Exposure ◽  
Isolated Lung ◽  
Injured Lung ◽  
Lung Liquid

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.

scholarly journals Dopamine increases lung liquid clearance during mechanical ventilation

2002 ◽  
Vol 283 (1) ◽  
pp. L136-L143 ◽  
Author(s):  
F. J. Saldías ◽  
A. P. Comellas ◽  
L. Pesce ◽  
E. Lecuona ◽  
J. I. Sznajder
Keyword(s):  
Mechanical Ventilation ◽  
Atpase Activity ◽  
Tidal Volume ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Short Term ◽  
Fluid Reabsorption ◽  
Alveolar Epithelial ◽  
Steady State Levels ◽  
Lung Liquid

Short-term mechanical ventilation with high tidal volume (HVT) causes mild to moderate lung injury and impairs active Na+ transport and lung liquid clearance in rats. Dopamine (DA) enhances active Na+ transport in normal rat lungs by increasing Na+-K+-ATPase activity in the alveolar epithelium. We examined whether DA would increase alveolar fluid reabsorption in rats ventilated with HVT for 40 min compared with those ventilated with low tidal volume (LVT) and with nonventilated rats. Similar to previous reports, HVT ventilation decreased alveolar fluid reabsorption by ∼50% ( P < 0.001). DA increased alveolar fluid reabsorption in nonventilated control rats (by ∼60%), LVT ventilated rats (by ∼55%), and HVT ventilated rats (by ∼200%). In parallel studies, DA increased Na+-K+-ATPase activity in cultured rat alveolar epithelial type II cells (ATII). Depolymerization of cellular microtubules by colchicine inhibited the effect of DA on HVT ventilated rats as well as on Na+-K+-ATPase activity in ATII cells. Neither DA nor colchicine affected the short-term Na+-K+-ATPase α1- and β1-subunit mRNA steady-state levels or total α1- and β1-subunit protein abundance in ATII cells. Thus we reason that DA improved alveolar fluid reabsorption in rats ventilated with HVT by upregulating the Na+-K+-ATPase function in alveolar epithelial cells.

Modulation of lung liquid clearance by isoproterenol in rat lungs

1998 ◽  
Vol 274 (5) ◽  
pp. L694-L701 ◽  
Author(s):  
F. Saldías ◽  
E. Lecuona ◽  
E. Friedman ◽  
M. L. Barnard ◽  
K. M. Ridge ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Basolateral Membrane ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Adrenergic Stimulation ◽  
Alveolar Type Ii Cells ◽  
Rat Lungs ◽  
Lung Liquid ◽  
Stimulation Of

β-Adrenergic agonists have been reported to increase lung liquid clearance by stimulating active Na+ transport across the alveolar epithelium. We studied mechanisms by which β-adrenergic isoproterenol (Iso) increases lung liquid clearance in isolated perfused fluid-filled rat lungs. Iso perfused through the pulmonary circulation at concentrations of 10−4 to 10−8 M increased lung liquid clearance compared with that of control lungs ( P < 0.01). The increase in lung liquid clearance was inhibited by the β-antagonist propranolol (10−5 M), the Na+-channel blocker amiloride (10−4 M), and the antagonist of Na-K-ATPase, ouabain (5 × 10−4 M). Colchicine, which inhibits cell microtubular transport of ion-transporting proteins to the plasma membrane, blocked the stimulatory effects of Iso on active Na+ transport, whereas the isomer lumicolchicine, which does not affect cell microtubular transport, did not inhibit Na+ transport. In parallel with these changes, the Na-K-ATPase α1-subunit protein abundance and activity increased in alveolar type II cells stimulated by 10−6 M Iso. Colchicine blocked the stimulatory effect of Iso and the recruitment of Na-K-ATPase α1-protein to the basolateral membrane of alveolar type II cells. Accordingly, Iso increased active Na+ transport and lung liquid clearance by stimulation of β-adrenergic receptors and probably by upregulation of apical Na+ channels and basolateral Na-K-ATPase mechanisms. Recruitment from intracellular pools and microtubular transport of Na+pumps to the plasma membrane participate in β-adrenergic stimulation of lung liquid clearance in rat lungs.

scholarly journals Bubble CPAP Support after Discontinuation of Mechanical Ventilation Protects Rat Lungs with Ventilator-Induced Lung Injury

Respiration ◽  
2016 ◽  
Vol 91 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Chun Shan Wu ◽  
Hsiu Chu Chou ◽  
Liang Ti Huang ◽  
Yen Kuang Lin ◽  
Chung Ming Chen
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Ventilator Induced Lung Injury ◽  
Rat Lungs ◽  
Bubble Cpap

Reticulocalbin 3 deficiency in alveolar epithelium attenuated LPS-induced ALI via NF-κB signaling

2021 ◽  
Vol 320 (4) ◽  
pp. L627-L639
Author(s):  
Xiaoqian Shi ◽  
Xiaojie An ◽  
Liu Yang ◽  
Zhipeng Wu ◽  
Danni Zan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Secretory Pathway ◽  
Alveolar Epithelium ◽  
Repair Process ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial

Acute respiratory distress syndrome (ARDS) is characterized by acute lung injury (ALI) secondary to an excessive alveolar inflammatory response. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein in the secretory pathway. We previously reported the indispensable role of Rcn3 in type II alveolar epithelial cells (AECIIs) during lung development and the lung injury repair process. In the present study, we further observed a marked induction of Rcn3 in the alveolar epithelium during LPS-induced ALI. In vitro alveolar epithelial (MLE-12) cells consistently exhibited a significant induction of Rcn3 accompanied with NF-κB activation in response to LPS exposure. We examined the role of Rcn3 in the alveolar inflammatory response by using mice with a selective deletion of Rcn3 in alveolar epithelial cells upon doxycycline administration. The Rcn3 deficiency significantly blunted the ALI and alveolar inflammation induced by intratracheal LPS instillation but not that induced by an intraperitoneal LPS injection (secondary insult); the alleviated ALI was accompanied by decreases in NF-κB activation and NLRP3 levels but not in GRP78 and cleaved caspase-3 levels. The studies conducted in MLE-12 cells consistently showed that Rcn3 knockdown blunted the activations of NF-κB signaling and NLRP3-dependent inflammasome upon LPS exposure. Collectively, these findings suggest a novel role for Rcn3 in regulating the alveolar inflammatory response to pulmonary infection via the NF-κB/NLRP3/inflammasome axis and shed additional light on the mechanism of ARDS/ALI.

scholarly journals Mitochondrial peptides cause proinflammatory responses in the alveolar epithelium via FPR-1, MAPKs, and AKT: a potential mechanism involved in acute lung injury

2018 ◽  
Vol 315 (5) ◽  
pp. L775-L786 ◽  
Author(s):  
Xue Zhang ◽  
Tao Wang ◽  
Zhi-Cheng Yuan ◽  
Lu-Qi Dai ◽  
Ni Zeng ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Specific Inhibitor ◽  
Alveolar Epithelium ◽  
Formyl Peptide Receptor ◽  
Potential Mechanism ◽  
Alveolar Epithelial

Acute lung injury (ALI) is characterized by alveolar epithelial damage and uncontrolled pulmonary inflammation. Mitochondrial damage-associated molecular patterns (DAMPs), including mitochondrial peptides [ N-formyl peptides (NFPs)], are released during cell injury and death and induce inflammation by unclear mechanisms. In this study, we have investigated the role of mitochondrial DAMPs (MTDs), especially NFPs, in alveolar epithelial injury and lung inflammation. In murine models of ALI, high levels of mitochondrial NADH dehydrogenase 1 in bronchoalveolar lavage fluid (BALF) were associated with lung injury scores and increased formyl peptide receptor (FPR)-1 expression in the alveolar epithelium. Cyclosporin H (CsH), a specific inhibitor of FPR1, inhibited lung inflammation in the ALI models. Both MTDs and NFPs upon intratracheal challenge caused accumulation of neutrophils into the alveolar space with elevated BALF levels of mouse chemokine KC, interleukin-1β, and nitric oxide and increased pulmonary FPR-1 levels. CsH significantly attenuated MTDs or NFP-induced inflammatory lung injury and activation of MAPK and AKT pathways. FPR1 expression was present in rat primary alveolar epithelial type II cells (AECIIs) and was increased by MTDs. CsH inhibited MTDs or NFP-induced CINC-1/IL-8 release and phosphorylation of p38, JNK, and AKT in rat AECII and human cell line A549. Inhibitors of MAPKs and AKT also suppressed MTD-induced IL-8 release and NF-κB activation. Collectively, our data indicate an important role of the alveolar epithelium in initiating immune responses to MTDs released during ALI. The potential mechanism may involve increase of IL-8 production in MTD-activated AECII through FPR-1 and its downstream MAPKs, AKT, and NF-κB pathways.

scholarly journals Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling

2014 ◽  
Vol 307 (1) ◽  
pp. L94-L105 ◽  
Author(s):  
Yoko Ito ◽  
Kelly Correll ◽  
John A. Schiel ◽  
Jay H. Finigan ◽  
Rytis Prekeris ◽  
...  
Keyword(s):  
Wound Healing ◽  
Growth Factor ◽  
Lung Injury ◽  
Hepatocyte Growth Factor ◽  
Wound Closure ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Alveolar Epithelial ◽  
Hepatocyte Growth

There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS.

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