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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/L932    most recent 00437.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Myerburg, M. M. Articles by Pilewski, J. M. Search for Related Content PubMed PubMed Citation Articles by Myerburg, M. M. Articles by Pilewski, J. M.

Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

¹Division of Pulmonary, Allergy, and Critical Care Medicine, ²Department of Pediatrics, ³Department of Cell Biology and Physiology, and ⁴Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 20 October 2007 ; accepted in final form 25 February 2008

Airway surface liquid (ASL) absorption is initiated by Na⁺ entry via epithelial Na⁺ channels (ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells (HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na⁺ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na⁺ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express >50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na⁺ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.

epithelial sodium channels; protease nexin 1; bronchial epithelial cultures; matriptase

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