Chloride secretion across adult alveolar epithelial cells contributes to cardiogenic edema

Londino, J.D.; Matalon, Sadis

doi:10.1073/pnas.1307480110

Cited by 10 publications

(8 citation statements)

References 24 publications

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“…As previously described (23), individual cells expressing GFP were briefly patched in whole‐cell configuration (24) using pipettes with an electrical resistance of 3‐5 mΩ. Pipette solution (mM): 135 KCl, 6 NaCl, 1 MgCl 2 , 0.5 EGTA, 10 HEPES, pH 7.2; Bath solution (mM): 135 NaCl, 2.7 KCl, 1.8CaCl 2 , 1 MgCl 2 , 5.5 glucose, and 10 HEPES, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…As previously described (23), individual cells expressing GFP were briefly patched in whole-cell configuration (24) using pipettes with an electrical resistance of 3-5m V. Pipette solution (mM): 1 3 5K C l ,6N a C l ,1M g C l 2 , 0.5 EGTA, 10 HEPES, pH 7.2; Bath solution (mM): 135 NaCl, 2.7 KCl, 1.8 CaCl 2 ,1MgCl 2 ,5.5glucose, and 10 HEPES, pH 7.4. Cells were firstperfusedwithbathsolutions containing forskolin (10 mM) and 3-isobutyl-1-methylxanthine (IBMX) (100 mM) (Sigma-Aldrich).…”

Section: Measurement Of Whole-cell Currents In Cellsmentioning

confidence: 99%

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Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

et al. 2015

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We sought to determine the mechanisms by which influenza infection of human epithelial cells decreases cystic fibrosis transmembrane conductance regulator (CFTR) expression and function. We infected human bronchial epithelial (NHBE) cells and murine nasal epithelial (MNE) cells with various strains of influenza A virus. Influenza infection significantly reduced CFTR short circuit currents (Isc) and protein levels at 8 hours postinfection. We then infected CFTR expressing human embryonic kidney (HEK)‐293 cells (HEK‐293 CFTRwt) with influenza virus encoding a green fluorescent protein (GFP) tag and performed whole‐cell and cell‐attached patch clamp recordings. Forskolin‐stimulated, GlyH‐101‐sensitive CFTR conductances, and CFTR open probabilities were reduced by 80% in GFP‐positive cells; Western blots also showed significant reduction in total and plasma membrane CFTR levels. Knockdown of the influenza matrix protein 2 (M2) with siRNA, or inhibition of its activity by amantadine, prevented the decrease in CFTR expression and function. Lysosome inhibition (bafilomycin‐A1), but not proteasome inhibition (lactacystin), prevented the reduction in CFTR levels. Western blots of immunoprecipitated CFTR from influenza‐infected cells, treated with BafA1, and probed with antibodies against lysine 63‐linked (K‐63) or lysine 48‐linked (K‐48) polyubiquitin chains supported lysosomal targeting. These results highlight CFTR damage, leading to early degradation as an important contributing factor to influenza infection‐associated ion transport defects.—Londino, J. D., Lazrak, A., Noah, J. W., Aggarwal, S., Bali, V., Woodworth, B. A., Bebok, Z., Matalon, S. Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection. FASEB J. 29, 2712–2725 (2015). http://www.fasebj.org

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Section: Methodsmentioning

confidence: 99%

Section: Measurement Of Whole-cell Currents In Cellsmentioning

confidence: 99%

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

et al. 2015

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“…During transit through the ER, improperly folded proteins, including some CFTR mutants and posttranslational modified CFTR, are polyubiquitinated through the linkage of lysine 48 or 29 (K48, K29) of the ubiquitin molecules and subsequently degraded by the proteasome. Upon exiting the ER, recycling and degradation of fully glycosylated plasma membrane CFTR are primarily regulated by polyubiquitination through the linkage between lysine 63, 11, or 6 (K63, K11, and K6) of the ubiquitin molecules, followed by lysosomal degra-dation (63). Several E3 ligases have been implicated in the degradation of CFTR including Nedd4 -2, c-cbl, CHIP, MARCH2, and RMA1/RNF5 (24,79).…”

Section: Influenza Virus M2 Is Necessary For the Inhibition Of Cftr Fmentioning

confidence: 99%

“…INFLUENZA VIRUSES INJURE LUNG ION CHANNELS onset of hydrostatic pulmonary edema, increased hydrostatic pulmonary pressure decreased active Na ϩ transport acutely and reversibly with little change in lung permeability and increased Cl Ϫ secretion through CFTR (63,94) that promoted fluid accumulation in the lung. Solymosi et al (94) proposed that inhibition of apical Na ϩ transport through ENaC changes the electrochemical gradient that may result in Cl Ϫ secretion through CFTR.…”

Section: L852mentioning

confidence: 99%

Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

Londino

Lazrak

Collawn

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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The cystic fibrosis transmembrane conductance regulator (CFTR) and the amiloride-sensitive epithelial sodium channels (ENaC) are located in the apical membranes of airway and alveolar epithelial cells. These transporters play an important role in the regulation of lung fluid balance across airway and alveolar epithelia by being the conduits for chloride (Cl) and bicarbonate ([Formula: see text]) secretion and sodium (Na) ion absorption, respectively. The functional role of these channels in the respiratory tract is to maintain the optimum volume and ionic composition of the bronchial periciliary fluid (PCL) and alveolar lining fluid (ALF) layers. The PCL is required for proper mucociliary clearance of pathogens and debris, and the ALF is necessary for surfactant homeostasis and optimum gas exchange. Dysregulation of ion transport may lead to mucus accumulation, bacterial infections, inflammation, pulmonary edema, and compromised respiratory function. Influenza (or flu) in mammals is caused by influenza A and B viruses. Symptoms include dry cough, sore throat, and is often followed by secondary bacterial infections, accumulation of fluid in the alveolar spaces and acute lung injury. The underlying mechanisms of flu symptoms are not fully understood. This review summarizes our present knowledge of how influenza virus infections alter airway and alveolar epithelial cell CFTR and ENaC function in vivo and in vitro and the role of these changes in influenza pathogenesis.

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“…Under worsening HF, as shown in the present study, there is a high pleural Cl concentration compared with the low Cl concentration in the normal physiological state, 27 , 28 suggesting that Cl has an active role in the formation of pleural fluid, in accordance with the “chloride theory”, which predicts that Cl is the key electrolyte for regulating the distribution of body fluid or water in each body compartment. 12 In fact, experimental studies have demonstrated the contribution of Cl to the formation of cardiogenic alveolar edema 38 , 39 or vascular endothelial glycocalyx swelling, 40 which supports the regulation of body water distribution by Cl − .…”

Section: Discussionmentioning

confidence: 75%

Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion　― Pathophysiologic Implications ―

Kataoka

2020

Circ Rep

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Background: There is scant clinical data of electrolyte analyses in the pleural fluid under heart failure (HF) pathophysiology. Methods and Results: This study retrospectively analyzed data from 17 consecutive patients who presented with pleural effusion and underwent thoracentesis. A diagnosis of worsening HF was established by clinical criteria (presentation, echocardiography, serum B-type natriuretic peptide, and response to therapy). Samples of non-heparinized pleural fluid and peripheral venous blood, obtained within 2 h of each other, were subjected to biochemical analysis. The source of pleural effusion was determined as transudate or exudate according to Light’s criteria. Fifteen patients (53% men; mean [±SD] age 85±11 years) had HF-associated pleural effusion, 10 of whom had transudative effusion and 5 who had exudative effusion (fulfilling only 1 [n=4] or both [n=1] lactate dehydrogenase criteria). The effusion-serum gradient (calculated by subtracting the serum electrolyte concentration from the effusion electrolyte concentration) was significantly higher for chloride (mean [±SD] 7.4±2.6 mEq/L; range 4–14 mEq/L) than sodium (0.9±1.4 mEq/L; ranging from −1 to 4 mEq/L) and potassium (−0.1±0.3 mEq/L; ranging from −0.8 to 0.2 mEq/L; P<0.001 for each). Conclusions: In HF-associated pleural effusion, the chloride concentration is higher in the pleural effusion than the serum, indicating that chloride may have an important role in the formation and retention of body fluid in the pleural space.

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Chloride secretion across adult alveolar epithelial cells contributes to cardiogenic edema

Cited by 10 publications

References 24 publications

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion　― Pathophysiologic Implications ―

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Chloride secretion across adult alveolar epithelial cells contributes to cardiogenic edema

Cited by 10 publications

References 24 publications

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

Influenza virus M2 targets cystic fibrosis transmembrane conductance regulator for lysosomal degradation during viral infection

Influenza virus infection alters ion channel function of airway and alveolar cells: mechanisms and physiological sequelae

Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion ― Pathophysiologic Implications ―

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Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion　― Pathophysiologic Implications ―