Due to necessary maintenance, Xenbase will be unavailable December 24-30, 2014. We apologize for the inconvenience.

Click on this message to dismiss it.
Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-39181
Am J Respir Cell Mol Biol. September 1, 2009; 41 (3): 261-70.

Alpha(1)-antitrypsin inhibits epithelial Na+ transport in vitro and in vivo.

Lazrak A , Nita I , Subramaniyam D , Wei S , Song W , Ji HL , Janciauskiene S , Matalon S .


Abstract
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.
Grant support: 5U01ES015676 NIEHS NIH HHS , HL031197 NHLBI NIH HHS , HL031197 NHLBI NIH HHS , HL031197 NHLBI NIH HHS , HL031197 NHLBI NIH HHS , HL031197 NHLBI NIH HHS , HL031197 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , HL051173 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017-04S1 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS , R01 HL087017 NHLBI NIH HHS

Genes referenced: ptch1 scnn1g
Antibodies referenced:
Morpholinos referenced:

My Xenbase: [ Log-in / Register ]
version: [3.3.1]


Major funding for Xenbase is provided by the National Institute of Child Health and Human Development, grant P41 HD064556