Contribution of CFTR to apical-basolateral fluid transport in cultured human alveolar epithelial type II cells

Fang, Xiaohui; Song, Yuanlin; Hirsch, Ján; Galietta, Luis J. V.; Pedemonte, Nicoletta; Zemans, Rachel L.; Dolganov, Gregory; Matthay, Michael A.

doi:10.1152/ajplung.00178.2005

Cited by 147 publications

(153 citation statements)

References 44 publications

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“…2A). This finding is essentially in line with the proposed facilitation of alveolar fluid clearance by Cl − uptake under physiological conditions (10). Conversely, Cl − -free lung perfusion selectively inhibited secretory fluid transport at elevated P LA (Fig.…”

Section: Resultssupporting

confidence: 88%

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Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Solymosi

Kaestle-Gembardt

Vadász

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Alveolar fluid clearance driven by active epithelial Na + and secondary Cl − absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na + channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl − secretion and alveolar Cl − influx were quantified by radionuclide tracing and alveolar Cl − imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl − secretion and alveolar Cl − influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na + -K + -Cl − cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR −/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl − secretion that were again CFTR-, NKCC-, and Na + -K + -ATPase-dependent. Our findings show a reversal of transepithelial Cl − and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl − and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.epithelial Cl − transport | pulmonary edema T raditionally, the formation of cardiogenic pulmonary edema has been attributed to passive fluid filtration across an intact alveolocapillary barrier along an increased hydrostatic pressure gradient. However, recent studies show that cardiogenic edema is critically regulated by active signaling processes. Activation of mechanosensitive endothelial ion channels increases lung vascular permeability (1), whereas alveolar epithelial cells lose their physiological ability to clear the distal airspaces from excess fluid by their capacity to actively transport ions across the epithelial barrier (2-4).In the intact lung, the predominant force driving alveolar fluid clearance is an active transepithelial Na + transport from the alveolar into the interstitial space. A major portion of the apical Na + entry is mediated by the amiloride-inhibitable epithelial Na + channel (ENaC), with basolateral Na + extrusion through the Na + -K + -ATPase (5). Cl − and water are considered to follow paracellularly for electroneutrality and osmotic balance. In cardiogenic lung edema, the physiological protection against alveolar flooding provided by an intact alveolar fluid clearance is largely attenuated (3, 4). Previously, ...

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Section: Resultssupporting

confidence: 88%

“…Depending on the actual electrochemical gradient, CFTR expressed in the apical plasma membrane can mediate both Cl − absorption and secretion by alveolar epithelial cells (10). We, therefore, tested whether alveolar secretion of Cl − and fluid at hydrostatic stress requires CFTR.…”

Section: Resultsmentioning

confidence: 99%

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Solymosi

Kaestle-Gembardt

Vadász

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Lungs were obtained from five adult males without lung disease who died after head trauma or cerebrovascular accident. Type II cells were isolated by our published methods (18,19). Freshly isolated human AT II cells were plated in the upper compartment of Transwells (0.4-mm pore size and collagen I coated; Costar, Corning) in DMEM-H21 and F-12 Ham's (1:1) plus 10% FBS.…”

Section: Primary Cultures Of Human At II Cellsmentioning

confidence: 99%

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Fang

Abbott

Cheng

et al. 2015

The Journal of Immunology

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123

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Previous studies demonstrated that bone marrow–derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of acute lung injury in animal models and in an ex vivo perfused human lung model. However, the mechanisms by which MSCs reduce lung injury are not well understood. In the present study, we tested the hypothesis that human MSCs promote the resolution of acute lung injury in part through the effects of a specialized proresolving mediator lipoxin A4 (LXA4). Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury (ALI) in mice led to improved survival (48 h), and blocking the LXA4 receptor with WRW4, a LXA4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA4 alone improved survival in mice, and it also significantly decreased the production of TNF-α and MIP-2 in bronchoalveolar lavage fluid. In summary, these experiments demonstrated two novel findings: human MSCs promote the resolution of lung injury in mice in part through the proresolving lipid mediator LXA4, and LXA4 itself should be considered as a therapeutic for acute respiratory distress syndrome.

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“…Although we have shown that TGF-␤1 inhibits basal and corticosteroid-stimulated alveolar fluid transport (22), the potential effect of TGF-␤1 on the ␤-adrenergic-stimulated alveolar fluid transport is still unknown. Recent experimental evidence convincingly demonstrated in mice and humans a role for the cystic fibrosis transmembrane conductance regulator (CFTR) in the ␤ 2 AR agonist-mediated stimulation of the alveolar epithelial fluid transport (23)(24)(25)(26)(27)(28)(29). Thus, the objective of this study was to examine the mechanisms by which TGF-␤1 would inhibit the ␤ 2 AR agonist-stimulated CFTR-dependent alveolar epithelial fluid transport.…”

Section: Acute Lung Injury (Ali)mentioning

confidence: 99%

Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

Roux

Carlès

Koh

et al. 2010

Journal of Biological Chemistry

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Exogenous or endogenous ␤ 2 -adrenergic receptor agonists enhance alveolar epithelial fluid transport via a cAMP-dependent mechanism that protects the lungs from alveolar flooding in acute lung injury. However, impaired alveolar fluid clearance is present in most of the patients with acute lung injury and is associated with increased mortality, although the mechanisms responsible for this inhibition of the alveolar epithelial fluid transport are not completely understood. Here, we found that transforming growth factor ␤1 (TGF-␤1), a critical mediator of acute lung injury, inhibits ␤ 2 -adrenergic receptor agonist-stimulated vectorial fluid and Cl ؊ transport across primary rat and human alveolar epithelial type II cell monolayers. This inhibition is due to a reduction in the cystic fibrosis transmembrane conductance regulator activity and biosynthesis mediated by a phosphatidylinositol 3-kinase (PI3K)-dependent heterologous desensitization and down-regulation of the ␤ 2 -adrenergic receptors. Consistent with these in vitro results, inhibition of the PI3K pathway or pretreatment with soluble chimeric TGF-␤ type II receptor restored ␤ 2 -adrenergic receptor agonist-stimulated alveolar epithelial fluid transport in an in vivo model of acute lung injury induced by hemorrhagic shock in rats. The results demonstrate a novel role for TGF-␤1 in impairing the ␤-adrenergic agonist-stimulated alveolar fluid clearance in acute lung injury, an effect that could be corrected by using PI3K inhibitors that are safe to use in humans.

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Contribution of CFTR to apical-basolateral fluid transport in cultured human alveolar epithelial type II cells

Cited by 147 publications

References 44 publications

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4

Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

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