title: Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium.
abstract: In cystic fibrosis (CF), the airway surface liquid (ASL) is depleted. We previously demonstrated that lipoxin A4 (LXA4) can modulate ASL height (ASLh) through actions on Cl(-) transport. Here, we report novel effects of lipoxin on the epithelial Na(+) channel ENaC in this response. ASL dynamics and ion transport were studied using live-cell confocal microscopy and short-circuit current measurements in CF (CuFi-1) and non-CF (NuLi-1) cell cultures. Low physiological concentrations of LXA4 in the picomolar range produced an increase in ASLh which was dependent on inhibition of an amiloride-sensitive Na(+) current and stimulation of a bumetanide-sensitive Cl(-) current. These ion transport and ASLh responses to LXA4 were blocked by Boc-2 an inhibitor of the specific LXA4 receptor ALX/FPR2. LXA4 affected the subcellular localization of its receptor and enhanced the localization of ALX/FPR2 at the apical membrane of CF cells. Our results provide evidence for a novel effect of low physiological concentrations of LXA4 to inhibit airway epithelial Na(+) absorption that results in an ASL height increase in CF airway epithelia.
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland Department of Respiratory Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Mazen
authors.initials: M
authors.lastname: Al-Alawi
authors.affiliation: National Children Research Centre, Dublin 12, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Buchanan
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Valia
authors.initials: V
authors.lastname: Verriere
authors.affiliation: National Children Research Centre, Dublin 12, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Higgins
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Olive
authors.initials: O
authors.lastname: McCabe
authors.affiliation: Department of Respiratory Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Costello
authors.affiliation: National Children Research Centre, Dublin 12, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: McNally
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland National Children Research Centre, Dublin 12, Ireland INSERM U661, Montpellier, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Urbach
authors.affiliation: Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Harvey
keywords: Cystic fibrosis; ENaC; lipoxin A4
references.citation: J Immunol. 1993 Nov 15;151(10):5704-15
references.pmid: 8228256
references.citation: Eur Respir J. 2006 Sep;28(3):581-7
references.pmid: 16807263
references.citation: Nat Immunol. 2005 Dec;6(12):1191-7
references.pmid: 16369558
references.citation: Mol Cell. 2001 Jul;8(1):149-58
references.pmid: 11511368
references.citation: Cell. 1998 Dec 23;95(7):1005-15
references.pmid: 9875854
references.citation: Nat Immunol. 2004 Apr;5(4):388-92
references.pmid: 15034576
references.citation: Methods Mol Med. 2002;70:479-92
references.pmid: 11917544
references.citation: J Clin Invest. 2000 May;105(10):1419-27
references.pmid: 10811849
references.citation: J Immunol. 1981 Sep;127(3):839-44
references.pmid: 6790618
references.citation: Science. 1989 Sep 8;245(4922):1066-73
references.pmid: 2475911
references.citation: J Lipid Mediat Cell Signal. 1995 Oct;12(2-3):293-306
references.pmid: 8777573
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 May;284(5):L844-54
references.pmid: 12676769
references.citation: PLoS One. 2012;7(5):e37746
references.pmid: 22662206
references.citation: Science. 1995 Aug 11;269(5225):847-50
references.pmid: 7543698
references.citation: N Engl J Med. 1999 Jul 15;341(3):156-62
references.pmid: 10403853
references.citation: FEBS Lett. 1997 Jan 6;400(3):341-4
references.pmid: 9009227
references.citation: Am J Pathol. 2002 Jun;160(6):2275-83
references.pmid: 12057930
references.citation: J Biol Chem. 2000 Aug 18;275(33):25372-80
references.pmid: 10837478
references.citation: Cell. 2010 Dec 10;143(6):911-23
references.pmid: 21145458
references.citation: Nat Genet. 1996 Mar;12(3):325-8
references.pmid: 8589728
references.citation: J Cell Biochem. 1985;27(3):241-53
references.pmid: 3838753
references.citation: Proc Natl Acad Sci U S A. 1984 Sep;81(17):5335-9
references.pmid: 6089195
references.citation: Am J Respir Cell Mol Biol. 2013 May;48(5):610-8
references.pmid: 23470626
references.citation: Blood. 2003 May 15;101(10):4140-7
references.pmid: 12560218
references.citation: Prostaglandins. 1997 Feb;53(2):107-37
references.pmid: 9112289
references.citation: Am J Pathol. 2006 Apr;168(4):1064-72
references.pmid: 16565483
references.citation: Curr Drug Targets. 2001 Dec;2(4):401-22
references.pmid: 11732639
references.citation: Eur Respir J. 2004 Jan;23(1):146-58
references.pmid: 14738247
references.citation: Respir Physiol Neurobiol. 2007 Dec 15;159(3):278-82
references.pmid: 17433793
references.citation: Acta Biomed. 2009 Aug;80(2):102-6
references.pmid: 19848046
references.citation: Proc Am Thorac Soc. 2004;1(1):66-70
references.pmid: 16113415
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Jan;296(1):L101-8
references.pmid: 18849442
references.citation: J Biol Chem. 2003 Mar 28;278(13):10879-84
references.pmid: 12500974
references.citation: Pflugers Arch. 2003 Jan;445(4):504-12
references.pmid: 12548397
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Jul 15;305(2):L193-201
references.pmid: 23686859
references.citation: J Cell Biol. 1984 Apr;98(4):1378-87
references.pmid: 6325470