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.

The Journal of Biological Chemistry
Dahis ManzanaresMatthias Salathe

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, Ca(2+)- 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 ...Continue Reading

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Citations

May 28, 2016·The Journal of Antimicrobial Chemotherapy·Lauren P LashuaJennifer M Bomberger
Nov 1, 2017·Scientific Reports·Stefanie KrickMatthias Salathe
Feb 3, 2018·Scientific Reports·Alison T LennoxMike M Myerburg
Feb 12, 2019·Annual Review of Physiology·Vivian Gonzalez-Perez, Christopher J Lingle
Oct 16, 2019·American Journal of Respiratory and Critical Care Medicine·Michael D KimMatthias Salathe
Dec 5, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Sayuri NodaYuji Imaizumi
Jun 3, 2020·International Journal of Molecular Sciences·Nilay MitashAgnieszka Swiatecka-Urban
Nov 24, 2017·Expert Opinion on Therapeutic Targets·Elizabeth L Kramer, John P Clancy
Feb 11, 2020·Frontiers in Medicine·Jaleesa GarthStefanie Krick
Jan 9, 2021·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Nikhil T AwatadeShafagh A Waters
Aug 1, 2020·The European Respiratory Journal·Charles D BengtsonMatthias Salathe
Feb 4, 2021·ERJ Open Research·Michael D KimMatthias Salathe
Apr 4, 2021·Genes·James A ReihillS Lorraine Martin
May 4, 2021·Frontiers in Pharmacology·Lisa KünziStefanie Krick

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