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.
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 amenable to treatment with clinically useful TGF-β1 inhibitors.
From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami, Miami, Florida 33136 and.
Dahis
D
Manzanares
From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami, Miami, Florida 33136 and.
Stefanie
S
Krick
From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami, Miami, Florida 33136 and.
Nathalie
N
Baumlin
From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami, Miami, Florida 33136 and.
John S
JS
Dennis
Cystic Fibrosis Center, University of North Carolina, Chapel Hill, North Carolina 27599.
Jean
J
Tyrrell
Cystic Fibrosis Center, University of North Carolina, Chapel Hill, North Carolina 27599.
Robert
R
Tarran
From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami, Miami, Florida 33136 and msalathe@med.miami.edu.
Matthias
M
Salathe
D000255:Adenosine Triphosphate / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000473:pathology*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D009079:Mucociliary Clearance / Q000187:drug effects; D009363:Neoplasm Proteins / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*
C539913:LRRC26 protein, human; D009363:Neoplasm Proteins; D024642:Potassium Channels, Voltage-Gated; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate; C093844:pirfenidone
BK; LRRC26; airway surface liquid; cilia; cystic fibrosis; epithelium; mallotoxin; pirfenidone; potassium channel; transforming growth factor beta (TGF-B)