title: Acute administration of ivacaftor to people with cystic fibrosis and aG551D-CFTRmutation reveals smooth muscle abnormalities.
abstract: BACKGROUND
  Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF.
  
  
  METHODS
  To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with theG551D-CFTRmutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone.
  
  
  RESULTS
  Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV.
  
  
  CONCLUSIONS
  Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle.
  
  
  BACKGROUND
  This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.
authors.affiliation: Department of Biomedical Engineering.|Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Adam
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Hisert
authors.affiliation: Department of Radiology and.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Dodd
authors.affiliation: National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland.
authors.forename: Brenda
authors.initials: B
authors.lastname: Grogan
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Launspach
authors.affiliation: Department of Biostatistics.
authors.forename: Janel K
authors.initials: JK
authors.lastname: Barnes
authors.affiliation: National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Gallagher
authors.affiliation: Department of Radiology, and.
authors.forename: Jered P
authors.initials: JP
authors.lastname: Sieren
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gross
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Fischer
authors.affiliation: Department of Biostatistics.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Cavanaugh
authors.affiliation: Department of Biomedical Engineering.|Department of Radiology, and.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics.|Howard Hughes Medical Institute, and.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: National Referral Centre for Adult Cystic Fibrosis, St. Vincent's University Hospital and University College Dublin School of Medicine, Dublin, Ireland.
authors.forename: Edward F
authors.initials: EF
authors.lastname: McKone
authors.affiliation: Department of Biomedical Engineering.|Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics.|Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz