XB-ART-39181Am J Respir Cell Mol Biol 2009 Sep 01;413:261-70. doi: 10.1165/rcmb.2008-0384OC.
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Alpha(1)-antitrypsin inhibits epithelial Na+ transport in vitro and in vivo.
A variety of studies have shown that Na(+) reabsorption across epithelial cells depends on the protease-antiprotease balance. Herein, we investigate the mechanisms by which alpha(1)-antitrypsin (A1AT), a major anti-serine protease in human plasma and lung epithelial fluid and lacking a Kunitz domain, regulates amiloride-sensitive epithelial Na(+) channel (ENaC) function in vitro and in vivo. A1AT (0.05 mg/ml = 1 microM) decreased ENaC currents across Xenopus laevis oocytes injected with human alpha,beta,gamma-ENaC (hENaC) cRNAs, and human lung Clara-like (H441) cells expressing native ENaC, in a partially irreversible fashion. A1AT also decreased ENaC single-channel activity when added in the pipette but not in the bath solutions of ENaC-expressing oocytes patched in the cell-attached mode. Incubation of A1AT with peroxynitrite (ONOO(-)), an oxidizing and nitrating agent, abolished its antiprotease activity and significantly decreased its ability to inhibit ENaC. Intratracheal instillation of normal but not ONOO(-)-treated A1AT (1 microM) in C57BL/6 mice also decreased Na(+)-dependent alveolar fluid clearance to the same level as amiloride. Incubation of either H441 cells or ENaC-expressing oocytes with normal but not ONOO(-)-treated A1AT decreased their ability to cleave a substrate of serine proteases. A1AT had no effect on amiloride-sensitive currents of oocytes injected with hENaC bearing Liddle mutations, presumably because these channels remain at the surface longer than the wild-type channels. These data indicate that A1AT may be an important modulator of ENaC activity and of Na(+)-dependent fluid clearance across the distal lung epithelium in vivo by decreasing endogenous protease activity needed to activate silent ENaC.
PubMed ID: 19131639
PMC ID: PMC2742747
Article link: Am J Respir Cell Mol Biol
Species referenced: Xenopus laevis
Genes referenced: ptch1 scnn1g serpina1
References [+] :
Adebamiro, Endogenous protease activation of ENaC: effect of serine protease inhibition on ENaC single channel properties. 2005, Pubmed