Airway surface dehydration by transforming growth factor β (TGF-β) in cystic fibrosis is due to decreased function of a voltage-dependent potassium channel and can be rescued by the drug pirfenidone

Dahis Manzanares, Stefanie Krick, Nathalie Baumlin, John S. Dennis, Jean Tyrrell, Robert Tarran, Matthias A Salathe

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Transforming growth factor β1 (TGF-β1) is not only elevated in airways of cystic fibrosis (CF) patients, whose airways are characterized by abnormal ion transport and mucociliary clearance, but TGF-β1 is also associated with worse clinical outcomes. Effective mucociliary clearance depends on adequate airway hydration, governed by ion transport. Apically expressed, large-conductance, Ca2+- and voltage-dependent K+ (BK) channels play an important role in this process. In this study, TGF-β1 decreased airway surface liquid volume, ciliary beat frequency, and BK activity in fully differentiated CF bronchial epithelial cells by reducing mRNA expression of the BK γ subunit leucine-rich repeat-containing protein 26 (LRRC26) and its function. Although LRRC26 knockdown itself reduced BK activity, LRRC26 overexpression partially reversed TGF-β1-induced BK dysfunction. TGF-β1-induced airway surface liquid volume hyper-absorption was reversed by the BK opener mallotoxin and the clinically useful TGF-β signaling inhibitor pirfenidone. The latter increased BK activity via rescue of LRRC26.Therefore, we propose that TGF-β1-induced mucociliary dysfunction in CF airways is associated with BK inactivation related to a LRRC26 decrease and is amenable to treatment with clinically useful TGF-β1 inhibitors.

Original languageEnglish (US)
Pages (from-to)25710-25716
Number of pages7
JournalJournal of Biological Chemistry
Volume290
Issue number42
DOIs
StatePublished - Oct 16 2015

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Potassium Channels
Transforming Growth Factors
Dehydration
Cystic Fibrosis
Leucine
Electric potential
Pharmaceutical Preparations
Mucociliary Clearance
Ion Transport
Proteins
Bridge clearances
Ions
Large-Conductance Calcium-Activated Potassium Channels
pirfenidone
Liquids
Hydration
Epithelial Cells
leucine-rich repeat proteins
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Airway surface dehydration by transforming growth factor β (TGF-β) in cystic fibrosis is due to decreased function of a voltage-dependent potassium channel and can be rescued by the drug pirfenidone. / Manzanares, Dahis; Krick, Stefanie; Baumlin, Nathalie; Dennis, John S.; Tyrrell, Jean; Tarran, Robert; Salathe, Matthias A.

In: Journal of Biological Chemistry, Vol. 290, No. 42, 16.10.2015, p. 25710-25716.

Research output: Contribution to journalArticle

Manzanares, Dahis ; Krick, Stefanie ; Baumlin, Nathalie ; Dennis, John S. ; Tyrrell, Jean ; Tarran, Robert ; Salathe, Matthias A. / Airway surface dehydration by transforming growth factor β (TGF-β) in cystic fibrosis is due to decreased function of a voltage-dependent potassium channel and can be rescued by the drug pirfenidone. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 42. pp. 25710-25716.
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