Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

Russo, Michael; Högenauer, Christoph; Coates, Stephen; Ana, Carol A. Santa; Porter, Jack L.; Rosenblatt, Randall L.; Emmett, Michael; Fordtran, John S.

doi:10.1172/jci17667

Cited by 24 publications

(14 citation statements)

References 53 publications

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“…The concordance between the claudin-7 and CFTR-deficient epithelium raises the possibility that claudin-7 may play a role in regulating apical chloride, perhaps by reducing paracellular chloride flux. Consistent with this, in CF there is a 4-fold decrease in passive intestinal chloride absorption that acts as a potential compensatory mechanism [120]. Whether this occurs in the airway and whether the paracellular route plays a role in regulating chloride balance is not known at present.…”

Section: Roles For Specific Claudins In Lung Epithelial Functionmentioning

confidence: 89%

Claudins: Gatekeepers of lung epithelial function

Schlingmann

Molina

Koval

2015

Seminars in Cell & Developmental Biology

154

108

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The lung must maintain a proper barrier between airspaces and fluid filled tissues in order to maintain lung fluid balance. Central to maintaining lung fluid balance are epithelial cells which create a barrier to water and solutes. The barrier function of these cells is mainly provided by tight junction proteins known as claudins. Epithelial barrier function varies depending on the different needs within the segments of the respiratory tree. In the lower airways, fluid is required to maintain mucociliary clearance, whereas in the terminal alveolar airspaces a thin layer of surfactant enriched fluid lowers surface tension to prevent airspace collapse and is critical for gas exchange. As the epithelial cells within the segments of the respiratory tree differ, the composition of claudins found in these epithelial cells is also different. Among these differences is claudin-18 which is uniquely expressed by the alveolar epithelial cells. Other claudins, notably claudin-4 and claudin-7, are more ubiquitously expressed throughout the respiratory epithelium. Claudin-5 is expressed by both pulmonary epithelial and endothelial cells. Based on in vitro and in vivo model systems and histologic analysis of lungs from human patients, roles for specific claudins in maintaining barrier function and protecting the lung from the effects of acute injury and disease are being identified. One surprising finding is that claudin-18 and claudin-4 control lung cell phenotype and inflammation beyond simply maintaining a selective paracellular permeability barrier. This suggests claudins have more nuanced roles for the control of airway and alveolar physiology in the healthy and diseased lung.

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Section: Roles For Specific Claudins In Lung Epithelial Functionmentioning

confidence: 89%

Claudins: Gatekeepers of lung epithelial function

Schlingmann

Molina

Koval

2015

Seminars in Cell & Developmental Biology

154

108

View full text Add to dashboard Cite

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“…The possibility that tight junctions can alter their charge selectivity as a compensatory adaptation to disease was recently reported in studies in intestine from patients with CF (35). Neonates with CF can develop dehydration of intestinal contents and inspissated intestinal obstruction (meconium ileus).…”

Section: Future Studies: Paracellular Transport In the Lungmentioning

confidence: 98%

“…This is theorized to result from the lack of CF transmembrane regulator-dependent secretion in the face of ongoing Na ϩ -dependent fluid absorption, resulting in hyperabsorption. The group led by John Fordtran (Baylor College of Medicine) recently reported that hyperabsorption in adult jejunum cannot be demonstrated (35). There is a marked decrease is paracellular Cl Ϫ permeability.…”

Section: Future Studies: Paracellular Transport In the Lungmentioning

confidence: 99%

The Role of Claudins in Determining Paracellular Charge Selectivity

Itallie¹

2004

Proceedings of the American Thoracic Society

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Tight junctions create regulated barriers in the paracellular space between epithelial cells, including those of the airway and alveolus. Junctions vary widely throughout the body in their electrical resistance and, to some extent, in their ionic charge selectivity. Paracellular differences complement transcellular transport to define overall water, ion, and solute movements. A large family of transmembrane proteins called claudins has recently been implicated in creating the variable properties of the junction. Here we highlight the evidence that claudins are functional components of the barrier. Supportive data include evidence from deletion of selected claudins in mice, human genetic diseases of claudins 14 and 16, and direct experimental tests of the hypothesis that the extracellular charged residues on claudins influence the passage of ions through the junction. Alterations in claudin expression profiles may contribute to epithelial lung dysfunction during infection and inflammation. Much work remains to be done in the molecular characterization of tight junctions in the lung in normal physiology and during pathologic processes.

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“…For example, previous studies in renal epithelial cells have shown that claudin-4 forms a high-resistance, lowpermeability tight junction that favors anion-selective paracellular ion movement (13,30). Others have reported that changes in claudin expression in response to environmental stimuli may account for changes in epithelial barrier properties in the gastrointestinal tract (23).…”

mentioning

confidence: 99%

Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

Wray¹,

Mao²,

Pan³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

139

156

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Intact alveolar barrier function is associated with better outcomes in acute lung injury patients; however, the regulation of alveolar epithelial paracellular transport during lung injury has not been extensively investigated. This study was undertaken to determine whether changes in tight junction claudin expression affect alveolar epithelial barrier properties and to determine the mechanisms of altered expression. In anesthetized mice exposed to ventilator-induced lung injury, claudin-4 was specifically induced among tight junction structural proteins. Real-time PCR showed an eightfold increase in claudin-4 expression in the lung injury model. To examine the role of this protein in barrier regulation, claudin-4 function was inhibited with small interfering RNA (siRNA) and a blocking peptide derived from the binding domain of Clostridium perfringens enterotoxin (CPE(BD)). Inhibition of claudin-4 decreased transepithelial electrical resistance but did not alter macromolecule permeability in primary rat and human epithelial cells. In mice, CPE(BD) decreased air space fluid clearance >33% and resulted in pulmonary edema during moderate tidal volume ventilation that did not induce edema in control peptide-treated mice. In vitro phorbol ester induced a ninefold increase in claudin-4 expression that was dependent on PKC activation and the JNK MAPK pathway. These data establish that changes in alveolar epithelial claudin expression influence paracellular transport, alveolar fluid clearance rates, and susceptibility to pulmonary edema. We hypothesize that increased claudin-4 expression early in acute lung injury represents a mechanism to limit pulmonary edema and that the regulation of alveolar epithelial claudin expression may be a novel target for acute lung injury therapy.

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Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect

Cited by 24 publications

References 53 publications

Claudins: Gatekeepers of lung epithelial function

Claudins: Gatekeepers of lung epithelial function

The Role of Claudins in Determining Paracellular Charge Selectivity

Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury

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