| First Author | Lazrak A | Year | 2014 |
| Journal | Am J Respir Cell Mol Biol | Volume | 50 |
| Issue | 5 | Pages | 953-62 |
| PubMed ID | 24303840 | Mgi Jnum | J:231992 |
| Mgi Id | MGI:5775700 | Doi | 10.1165/rcmb.2013-0215OC |
| Citation | Lazrak A, et al. (2014) Inter-alpha-inhibitor blocks epithelial sodium channel activation and decreases nasal potential differences in DeltaF508 mice. Am J Respir Cell Mol Biol 50(5):953-62 |
| abstractText | Increased activity of lung epithelial sodium channels (ENaCs) contributes to the pathophysiology of cystic fibrosis (CF) by increasing the rate of epithelial lining fluid reabsorption. Inter-alpha-inhibitor (IalphaI), a serum protease inhibitor, may decrease ENaC activity by preventing its cleavage by serine proteases. High concentrations of IalphaI were detected in the bronchoalveolar lavage fluid (BALF) of children with CF and lower airway diseases. IalphaI decreased amiloride-sensitive (IENaC) but not cAMP-activated Cl(-) currents across confluent monolayers of rat ATII, and mouse nasal epithelial cells grew in primary culture by 45 and 25%, respectively. Changes in IENaC by IalphaI in ATII cells were accompanied by increased levels of uncleaved (immature) surface alpha-ENaC. IalphaI increased airway surface liquid depth overlying murine nasal epithelial cells to the same extent as amiloride, consistent with ENaC inhibition. Incubation of lung slices from C57BL/6, those lacking phenylalanine at position 508 (F508), or CF transmembrane conductance regulator knockout mice with IalphaI for 3 hours decreased the open probability of their ENaC channels by 50%. F508 mice had considerably higher levels the amiloride-sensitive fractions of ENaC nasal potential difference (ENaC-NPD) than wild-type littermates and only background levels of IalphaI in their BALF. A single intranasal instillation of IalphaI decreased their ENaC-NPD 24 hours later by 25%. In conclusion, we show that IalphaI is present in the BALF of children with CF, is an effective inhibitor of ENaC proteolysis, and decreases ENaC activity in lung epithelial cells of F508 mice. |
