Alveolar Epithelial Ion and Fluid Transport

Folkesson, Hans G.; Matthay, Michael A.

doi:10.1165/rcmb.2006-0080sf

Cited by 98 publications

(98 citation statements)

References 132 publications

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“…CFTR, which is expressed in the apical membrane of both alveolar types I (14) and II (10) cells, may facilitate both absorption or secretion of Cl − depending on the actual electrochemical gradient. Under conditions of stimulated fluid absorption, CFTR constitutes a ratelimiting factor for alveolar fluid clearance (9,16). Here, CFTR mediated alveolar fluid clearance at physiological pressures, which was shown by reduced absorptive fluid transport and an increase in wet-to-dry weight ratio in glibenclamide-and CFTR inh -172-treated isolated rat lungs or isolated lungs of CFTR KO mice.…”

Section: Discussionmentioning

confidence: 95%

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: Discussionmentioning

confidence: 95%

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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Section: Alveolar Fluid Transportmentioning

confidence: 99%

“…However, studies using specific aquaporin-null mice have demonstrated that these channels do not have significant roles in alveolar fluid absorption despite their importance in osmotically driven water movement across epithelial and endothelial cell barriers in the lung [10][11][12][13][14][15]. Cl − is secreted into the alveolar space via the cystic fibrosis transmembrane regulator (CFTR) [16]; this receptor also plays a role in cAMP-mediated fluid transport [17,18].In a study of alveolar fluid clearance rates by Ware and Matthay, the majority of patients (56%) with ALI had impaired alveolar fluid clearance, and patients with maximal alveolar fluid clearance had significantly lower mortality and a shorter duration of mechanical ventilation [19]. Alveolar fluid clearance can be enhanced using β-adrenergic agonists that stimulate Na + transport via the basolateral ATPases [20].…”

mentioning

confidence: 99%

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Manicone¹

2009

Expert Review of Clinical Immunology

114

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Acute lung injury (ALI) is a clinical disease marked by respiratory failure due to disruption of the epithelial and endothelial barrier, flooding of the alveolar compartment with protein-rich fluid and recruitment of neutrophils into the alveolar space. ALI affects approximately 200,000 patients annually in the USA and results in approximately 75,000 deaths. It is associated with prolonged mechanical ventilation, intensive medical care, high morbidity and mortality, and rising healthcare costs. Owing to its impact on public health, great strides have been made towards understanding the pathobiology of ALI to affect outcome. This review will focus on the role of the epithelial cell in the pathogenesis and resolution of ALI and the role of various inflammatory mediators in ALI. Keywordsβ2-agonist; acute lung injury; acute respiratory distress syndrome; chemokine; cytokine; epithelial cell; inflammation; methylprednisolone; neutrophil; salbutamol; steroid; ventilator-induced lung injuryAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) was first described in 1967 by Ashbaugh and colleagues in a group of 12 patients who shared a constellation of clinical symptoms including acute respiratory distress, hypoxemia refractory to supplemental oxygen, decreased lung compliance and diffuse pulmonary infiltrates [1]. Since this first description, the clinical criteria have evolved to include acute onset of respiratory distress, bilateral pulmonary infiltrates seen on chest radiographs, absence of left-sided heart failure and hypoxemia, with the severity of hypoxemia distinguishing ALI and ARDS (Box 1) [2]. Extrapolating from recent epidemiologic studies using these criteria, ALI affects about 200,000 patients annually in the USA and results in approximately 75,000 deaths [3]. This disease, which can be caused by common events such as pneumonia, sepsis and trauma, results in high morbidity, mortality and healthcare expenditures associated with prolonged mechanical ventilation and intensive care. Because of its impact on public health and patient outcomes, great strides have been made towards understanding the pathobiology of ALI.When defined broadly to include all processes related to defense against microbes, other environmental insults and injury, a wide variety of cell types and proteins participate in inflammation and immunity. Leukocytes are the paradigmatic inflammatory cell type, but they are not the only cells that function in defense and immunity. The epithelial lining of all tissues forms a continuous barrier to the environment and is the first line of defense against infectious agents and toxins. Though specialized to serve distinct functions among tissues, epithelial cells respond similarly to injury and infection, and regulate leukocyte influx through the production of proinflammatory cytokines, chemokines and other factors that modulate chemokine gradients and effect leukocyte migration. This review will focus on the role of the pulmonary epithelium and inflammatory mediators in ALI. More s...

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“…PQ uptake is significantly prevented when extracellular sodium is reduced (Dinis-Oliveira et al, 2006). The amiloride-sensitive cation channel is a major sodium channel, and Na + /K + -ATPase is important for its activation (Dada and Sznajder, 2003;Eaton et al, 2004;Egli et al, 2004;Folkesson and Matthay, 2006;Kemp and Kim, 2004;Planès, et al, 2005;Matalon et al, 2002), as are potassium channels (O'Grady and Lee, 2003). The gene expression alterations of the Na + /Cl − -dependent neurotransmitter transporter gene, Slc17a1, Kcne1, Kcna1, Kcna4, Scn4a, Scn2b, Atp1a2, Accn2, and Accn3 could indicate changes in these functions.…”

Section: Discussionmentioning

confidence: 99%

“…ANP plays a pivotal role in urine volume and electrolyte homeostasis through potent biological effects including natriuresis, diuresis, and vasorelaxation. Besides being a target organ for ANP of atrial origin, the lung is also a site of bioactive ANP synthesis and release (Folkesson and Matthay, 2006). ANP increases alveolar epithelial permeability and decreases active Na + transport, thus decreasing alveolar fluid clearance (Olivera et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

et al. 2007

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-Although paraquat (PQ) is widely known to induce pulmonary fibrosis, the molecular mechanisms are poorly understood. Therefore, to bring a new dimension to the elucidation of the mechanisms, we conducted microarray experiments to investigate the expression profiles of 1,090 genes in the lungs during the progressive phase of PQ-induced pulmonary fibrosis in rats. After several s.c. injections of PQ, rats were divided into a fibrogenic group and a non-fibrogenic group. Time-course gene expression analysis of the fibrogenic group showed altered gene regulation throughout the experimental period. The expression levels of many cell membrane channel, transporter, and receptor genes were substantially altered. These genes were classified into two categories: polyamine transporter-and electrolyte/fluid balance-related genes. Moreover, comparative analysis of the fibrogenic and the non-fibrogenic group revealed 36 genes with significantly different patterns of expression, including the pro-apoptotic gene Bad. This indicates that Bad is a key factor in apoptosis and that apoptosis provides a major turning point in PQ-induced pulmonary fibrosis. Notably, subtypes of transforming growth factor (TGF)-β genes that are considered to play a pivotal role in fibrogenesis showed no differences in expression between the two groups, though TGF-β3 was markedly induced in both groups. These results provide novel and extensive insights into the molecular mechanisms that lead to pulmonary fibrosis after exposure to PQ.

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Alveolar Epithelial Ion and Fluid Transport

Cited by 98 publications

References 132 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

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

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