Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2010

Open Access 01-12-2010 | Research

Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells

Authors: Virginie Prulière-Escabasse, Christine Clerici, Grégoire Vuagniaux, Andre Coste, Estelle Escudier, Carole Planès

Published in: Respiratory Research | Issue 1/2010

Login to get access

Abstract

Background

Hyperactivity of the epithelial sodium (Na+) channel (ENaC) and increased Na+ absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin-like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na+ reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown.

Methods

We evaluated by short-circuit current (I sc) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients.

Results

Neither hNE nor EPI-hNE4 treatments did modify I sc in control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased I sc by 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate I sc, an effect which was blocked by EPI-hNE4.

Conclusions

These results indicate that hNE does activate ENaC and transepithelial Na+ transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways.
Literature
1.
Boucher RC: New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004, 23:146–158.CrossRefPubMed
2.
Canessa C, Horisberger J-D, Rossier BC: Epithelial sodium channel related to proteins involved in neurodegeneration. Nature (Lond) 1993, 361:467–470.CrossRef
3.
Canessa C, Schild L, Buell G, Thorens B, Gautschi I, Horisberger J-D, Rossier BC: Amiloride-sensitive epithelial Na + channel is made of three homologous subunits. Nature (Lond) 1994, 367:463–467.CrossRef
4.
Mall M, Bleich M, Greger R, Schreiber R, Kunzelmann K: The amiloride inhibitable Na + conductance is reduced by CFTR in normal but not in cystic fibrosis airways. J Clin Invest 1998, 102:15–21.CrossRefPubMedPubMedCentral
5.
König J, Schreiber R, Voelcker T, Mall M, Kunzelmann K: The cystic fibrosis transmembrane conductance regulator (CFTR) inhibits ENaC through an increase in the intracellular Cl - concentration. EMBO reports 2001, 21:1047–1051.CrossRef
6.
Mall M, Grubb BR, Harkema JR, O'neal WK, Boucher RC: Increased airway epithelial Na+ absorption produces cystic-fibrosis-like lung disease in mice. Nat Med 2004, 10:487–93.CrossRefPubMed
7.
Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002, 82:569–600.CrossRefPubMed
8.
9.
Rossier BC, Stutts MJ: Activation of the epithelial sodium channel (ENaC) by serine proteases. Annu Rev Physiol 2009, 71:361–379.CrossRefPubMed
10.
Vallet V, Chraibi A, Gaeggeler H-P, Horisberger J-D, Rossier BC: An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 1997, 389:607–610.CrossRefPubMed
11.
Vallet V, Pfister C, Loffing J, Rossier BC: Cell-surface expression of the channel activating protease xCAP-1 is required for activation of ENaC in the Xenopus oocyte. J Am Soc Nephrol 2002,13(3):588–94.PubMed
12.
Vuagniaux G, Vallet V, Fowler Jaeger N, Pfister C, Bens M, Farman N, Courtois-Coutry N, Vandewalle A, Rossier BC, Hummler E: Activation of the amiloride-sensitive epithelial sodium channel by the serine protease mCAP1 expressed in a mouse cortical collecting duct cell line. J Am Soc Nephrol 2000, 11:828–834.PubMed
13.
Adachi M, Kitamura K, Miyoshi T, Narikiyo T, Iwashita K, Shiraishi N, Nonoguchi H, Tomita K: Activation of epithelial sodium channels by prostasin in Xenopus oocytes. J Am Soc Nephrol 2001,2(6):1114–21.
14.
Vuagniaux G, Vallet V, Fowler Jaeger N, Hummler E, Rossier BC: Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucose-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol 2002, 120:191–201.CrossRefPubMedPubMedCentral
15.
Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE: Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 2002, 277:8338–8345.CrossRefPubMed
16.
Guipponi M, Vuagniaux G, Wattenhofer M, Shibuya K, Vazquez M, Dougherty L, Scamuffa N, Guida E, Okui M, Rossier C, Hancock M, Buchet K, Reymond A, Hummler E, Marzella PL, Kudoh J, Shimizu N, Scott HS, Antonarakis SE, Rossier BC: The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet 2002,11(23):2829–36.CrossRefPubMed
17.
Okumura Y, Nishikawa M, Cui P, Shiota M, Nakamura Y, Adachi M, Kitamura K, Tomita K, Kido H: Cloning and characterization of a transmembrane-type serine protease from rat kidney, a new sodium channel activator. J Biol Chem 2003,384(10–11):1483–95.
18.
Bruns JB, Carattino MD, Sheng S, Maarouf AB, Weisz OA, Pilewski JM, Hughey RP, Kleyman TR: Epithelial Na + channels are fully activated by furin- and prostasin-dependent release of an inhibitory peptide from the gamma-subunit. J Biol Chem 2007,282(9):6153–60.CrossRefPubMed
19.
Chraïbi A, Vallet V, Firsov D, Hess SK, Horisberger JD: Protease modulation of the activity of the epithelial sodium channel expressed in Xenopus oocytes. J Gen Physiol 1998,111(1):127–38.CrossRefPubMedPubMedCentral
20.
Caldwell RA, Boucher RC, Stutts MJ: Neutrophil elastase activates near-silent epithelial Na + channels and increases airway epithelial Na + transport. Am J Physiol Lung Cell Mol Physiol 2005, 288:L813-L819.CrossRefPubMed
21.
Liu L, Hering-Smith KS, Schiro FR, Hamm LL: Serine protease activity in m-1 cortical collecting duct cells. Hypertension 2002,39(4):860–4.CrossRefPubMed
22.
Verghese GM, Tong ZY, Bhagwandin V, Caughey GH: Mouse prostasin gene structure, promoter analysis, and restricted expression in lung and kidney. Am J Respir Cell Mol Biol 2004,30(4):519–29.CrossRefPubMed
23.
Planès C, Leyvraz C, Uchida T, Angelova MA, Vuagniaux G, Hummler E, Matthay MA, Clerici C, Rossier BC: In vitro and in vivo regulation of transepithelial lung alveolar sodium transport by serine proteases. Am J Physiol Lung Cell Mol Physiol 2005, 288:L1099-L1109.CrossRefPubMed
24.
Planès C, Randrianarison NH, Charles RP, Frateschi S, Cluzeaud F, Vuagniaux G, Soler P, Clerici C, Rossier BC, Hummler E: ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1. EMBO Mol Med 2010,2(1):26–37.CrossRefPubMedPubMedCentral
25.
Bridges RJ, Newton BB, Pilewski JM, Devor DC, Poll CT, Hall RL: Na + transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39–9437. Am J Physiol Lung Cell Mol Physiol 2001, 281:L16-L23.PubMed
26.
Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH: Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2004,287(5):L928–35.CrossRefPubMed
27.
Prulière-Escabasse V, Fanen P, Dazy AC, Lechapt-Zalcman E, Rideau D, Edelman A, Escudier E, Coste A: TGF-β1 downregulates CFTR expression and function in nasal polyps of non-CF patients. Am J Physiol Lung Cell Mol Physiol 2005, 288:L77-L83.CrossRefPubMed
28.
Mall M, Harkema JR, Trojanek JB, Treis D, Livraghi A, Schubert S, Zhou Z, Kreda SM, Tilley SL, Hudson EJ, O'Neal W, Boucher RC: Development of chronic bronchitis and emphysema in beta-epithelial Na+ channel overexpressing mice. Am J Respir Crit Care Med 2008,177(7):730–42.CrossRefPubMed
29.
Swystun V, Chen L, Factor P, Siroky B, Bell PD, Matalon S: Apical trypsin increases ion transport and resistance by a phospholipase C-dependent rise of Ca 2+ . Am J Physiol Lung Cell Mol Physiol 2005, 288:L820–30.CrossRefPubMed
30.
Harris M, Firsov D, Vuagniaux G, Stutts MJ, Rossier BC: A novel neutrophil elastase inhibitor prevents elastase activation and surface cleavage of the epithelial sodium channel expressed in Xenopus laevis oocytes. J Biol Chem 2007,282(1):58–64.CrossRefPubMed
31.
Myerburg MM, Butterworth MB, McKenna EE, Peters KW, Frizzell RA, Kleyman TR, Pilewski JM: Airway surface liquid volume regulates ENaC by altering the serine protease-protease inhibitor balance. A mechanism for sodium hyperaborption in cystic fibrosis. J Biol Chem 2006,281(38):27942–27949.CrossRefPubMed
32.
Tuyen DG, Kitamura K, Adachi M, Miyoshi T, Wakida N, Nagano J, Nonoguchi H, Tomita K: Inhibition of prostasin expression by TGF-β1 in renal epithelial cells. Kidney Int 2005, 67:193–200.CrossRefPubMed
33.
Barmeyer C, Amasheh S, Tavalali S, Mankertz J, Zeitz M, Fromm M, Schulzke JD: IL-1beta and TNFalpha regulate sodium absorption in rat distal colon. Biochem Biophys Res Com 2004,317(2):500–7.CrossRefPubMed
Metadata
Title
Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells
Authors
Virginie Prulière-Escabasse
Christine Clerici
Grégoire Vuagniaux
Andre Coste
Estelle Escudier
Carole Planès
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2010
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-11-141

Other articles of this Issue 1/2010

Respiratory Research 1/2010 Go to the issue

Research

Cytotoxic T cells expressing the co-stimulatory receptor NKG2 D are increased in cigarette smoking and COPD

Research

Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients

Research

Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-β1 in normal human lung fibroblasts (NHLF)

Research

Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial

Research

Decreased Toll-like receptor 8 expression and lower TNF-alpha synthesis in infants with acute RSV infection

Research

Isolation and characterization of microparticles in sputum from cystic fibrosis patients
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits