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 language | English (US) |
|---|---|
| Pages (from-to) | 25710-25716 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 290 |
| Issue number | 42 |
| DOIs | |
| State | Published - Oct 16 2015 |
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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 journal › Article
}
TY - JOUR
T1 - 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
AU - Manzanares, Dahis
AU - Krick, Stefanie
AU - Baumlin, Nathalie
AU - Dennis, John S.
AU - Tyrrell, Jean
AU - Tarran, Robert
AU - Salathe, Matthias A
PY - 2015/10/16
Y1 - 2015/10/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84944400951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944400951&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.670885
DO - 10.1074/jbc.M115.670885
M3 - Article
C2 - 26338706
AN - SCOPUS:84944400951
VL - 290
SP - 25710
EP - 25716
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 42
ER -