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J. Biol. Chem., Vol. 282, Issue 1, 58-64, January 5, 2007

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A Novel Neutrophil Elastase Inhibitor Prevents Elastase Activation and Surface Cleavage of the Epithelial Sodium Channel Expressed in Xenopus laevis Oocytes^*

Michael Harris, Dmitri Firsov, Grégoire Vuagniaux, M. Jackson Stutts^¶, and Bernard C. Rossier¹

From the Département de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland, Debiopharm SA, CH-1000 Lausanne, Switzerland, and ^¶University of North Carolina, Chapel Hill, North Carolina 27599-7248

The amiloride-sensitive epithelial sodium channel (ENaC) constitutes a limiting step in sodium reabsorption across distal airway epithelium and controlling mucociliary clearance. ENaC is activated by serine proteases secreted in the extracellular milieu. In cystic fibrosis lungs, high concentrations of secreted neutrophil elastase (NE) are observed. hNE could activate ENaC and contribute to further decreased mucociliary clearance. The aims of this study were (i) to test the ability of an engineered human neutrophil elastase inhibitor (EPI-hNE4) to specifically inhibit the elastase activation of ENaC-mediated amiloride-sensitive currents (I_Na) and (ii) to examine the effect of elastase on cell surface expression of ENaC and its cleavage pattern (exogenous proteolysis). Oocytes were exposed to hNE (10–100 µg/ml) and/or trypsin (10 µg/ml) for 2–5 min in the presence or absence of EPI-hNE4 (0.7 µM). hNE activated I_Na 3.6-fold (p < 0.001) relative to non-treated hENaC-injected oocytes. EPI-hNE4 fully inhibited hNE-activated I_Na but had no effect on trypsin- or prostasin-activated I_Na. The co-activation of I_Na by hNE and trypsin was not additive. Biotinylation experiments revealed that cell surface ENaC (but not or ENaC) exposed to hNE for 2 min was cleaved (as a 67-kDa fragment) and correlated with increased I_Na. The elastase-induced exogenous proteolysis pattern is distinct from the endogenous proteolysis pattern induced upon preferential assembly, suggesting a causal relationship between ENaC cleavage and ENaC activation, taking place at the plasma membrane.

Received for publication, May 30, 2006 , and in revised form, October 17, 2006.

^* This work was supported by grants from the Novartis Foundation in 2003 (to B. C. R.) and the Swiss National Foundation (3100-061966 (to B. C. R.) and 3100A0-105592 (to D. F.)). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dépt. de Pharmacologie et de Toxicologie, Université de Lausanne, 27, Rue du Bugnon, CH-1005 Lausanne, Switzerland. Tel.: 4121-692-5351; Fax: 4121-692-5355; E-mail: Bernard.Rossier{at}unil.ch.

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