PMID- 26338706
OWN - NLM
STAT- MEDLINE
DCOM- 20160216
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 42
DP  - 2015 Oct 16
TI  - Airway Surface Dehydration by Transforming Growth Factor beta (TGF-beta) in Cystic 
      Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel 
      and Can Be Rescued by the Drug Pirfenidone.
PG  - 25710-6
LID - 10.1074/jbc.M115.670885 [doi]
AB  - Transforming growth factor beta1 (TGF-beta1) is not only elevated in airways of cystic 
      fibrosis (CF) patients, whose airways are characterized by abnormal ion transport 
      and mucociliary clearance, but TGF-beta1 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-beta1 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 gamma subunit leucine-rich repeat-containing 
      protein 26 (LRRC26) and its function. Although LRRC26 knockdown itself reduced BK 
      activity, LRRC26 overexpression partially reversed TGF-beta1-induced BK dysfunction. 
      TGF-beta1-induced airway surface liquid volume hyper-absorption was reversed by the 
      BK opener mallotoxin and the clinically useful TGF-beta signaling inhibitor 
      pirfenidone. The latter increased BK activity via rescue of LRRC26. Therefore, we 
      propose that TGF-beta1-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-beta1 inhibitors.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Manzanares, Dahis
AU  - Manzanares D
AD  - From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 
      University of Miami, Miami, Florida 33136 and.
FAU - Krick, Stefanie
AU  - Krick S
AD  - From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 
      University of Miami, Miami, Florida 33136 and.
FAU - Baumlin, Nathalie
AU  - Baumlin N
AD  - From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 
      University of Miami, Miami, Florida 33136 and.
FAU - Dennis, John S
AU  - Dennis JS
AD  - From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 
      University of Miami, Miami, Florida 33136 and.
FAU - Tyrrell, Jean
AU  - Tyrrell J
AD  - Cystic Fibrosis Center, University of North Carolina, Chapel Hill, North Carolina 
      27599.
FAU - Tarran, Robert
AU  - Tarran R
AD  - Cystic Fibrosis Center, University of North Carolina, Chapel Hill, North Carolina 
      27599.
FAU - Salathe, Matthias
AU  - Salathe M
AD  - From the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 
      University of Miami, Miami, Florida 33136 and msalathe@med.miami.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150903
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (LRRC26 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Potassium Channels, Voltage-Gated)
RN  - 0 (Pyridones)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - D7NLD2JX7U (pirfenidone)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Bronchi/drug effects/*pathology
MH  - Cystic Fibrosis/drug therapy/*metabolism/pathology
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Mucociliary Clearance/drug effects
MH  - Neoplasm Proteins/genetics
MH  - Potassium Channels, Voltage-Gated/*physiology
MH  - Pyridones/*pharmacology/therapeutic use
MH  - Transforming Growth Factor beta1/antagonists & inhibitors/*physiology
PMC - PMC4646213
OTO - NOTNLM
OT  - BK
OT  - LRRC26
OT  - airway surface liquid
OT  - cilia
OT  - cystic fibrosis
OT  - epithelium
OT  - mallotoxin
OT  - pirfenidone
OT  - potassium channel
OT  - transforming growth factor beta (TGF-B)
EDAT- 2015/09/05 06:00
MHDA- 2016/02/18 06:00
PMCR- 2016/10/16
CRDT- 2015/09/05 06:00
PHST- 2015/06/09 00:00 [received]
PHST- 2015/09/05 06:00 [entrez]
PHST- 2015/09/05 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
PHST- 2016/10/16 00:00 [pmc-release]
AID - S0021-9258(20)44584-3 [pii]
AID - M115.670885 [pii]
AID - 10.1074/jbc.M115.670885 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Oct 16;290(42):25710-6. doi: 10.1074/jbc.M115.670885. Epub 2015 
      Sep 3.