Abstract
Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to β2-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by β2-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.
Highlights
Active transepithelial sodium (Naþ) transport by alveolar epithelial cells (AEC) is a driving force for reabsorption of fluid from the alveolar space, a function which accounts for the ability of the lung to remove alveolar fluid at the time of birth and represents the main mechanism for alveolar oedema resolution (Basset et al 1987; Hummler et al, 1996; Matthay et al,(1) Departement de Pharmacologie et de Toxicologie, Universite de Lausanne, Lausanne, Switzerland.(2) INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon, CRB3, Paris, France.1982, 2002)
Quantitative qRT-PCR experiments evidenced a 95% decrease in CAP1/Prss8 mRNA transcript expression in AEC isolated from knockout mice, whereas expression of mRNA transcripts encoding CAP2/Tmprss4 or CAP3/Prss14 did not differ between groups (Fig 1D)
The nonspecific serine protease inhibitor aprotinin completely suppressed the terbutaline-induced stimulation of alveolar fluid clearance (AFC) in control mice, but was without effect in knockout mice. These results suggest that CAP1 participates in the stimulation of epithelial Naþ channel (ENaC) and AFC induced by b-agonists, and that in the absence of CAP1, nonepithelial soluble serine proteases such as human neutrophil elastase (hNE) can substitute for endogenous CAP1
Summary
Active transepithelial sodium (Naþ) transport by alveolar epithelial cells (AEC) is a driving force for reabsorption of fluid from the alveolar space, a function which accounts for the ability of the lung to remove alveolar fluid at the time of birth and represents the main mechanism for alveolar oedema resolution (Basset et al 1987; Hummler et al, 1996; Matthay et al,(1) Departement de Pharmacologie et de Toxicologie, Universite de Lausanne, Lausanne, Switzerland.(2) INSERM, U773, Centre de Recherche Biomedicale Bichat-Beaujon, CRB3, Paris, France.1982, 2002). Active transepithelial sodium (Naþ) transport by alveolar epithelial cells (AEC) is a driving force for reabsorption of fluid from the alveolar space, a function which accounts for the ability of the lung to remove alveolar fluid at the time of birth and represents the main mechanism for alveolar oedema resolution The amiloride-sensitive epithelial Naþ channel (ENaC) (Canessa et al, 1993, 1994) composed of three homologous subunits (a, b and g) is expressed in type 1 and 2 AEC and plays a major role in Naþ absorption, representing in vivo a limiting factor for lung fluid clearance (Eaton et al, 2009; Hummler et al, 1996; Johnson et al, 2006; Matthay et al, 2002).
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