Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities
Ryan J. Adam, … , Edward F. McKone, David A. Stoltz
Ryan J. Adam, … , Edward F. McKone, David A. Stoltz
Published April 7, 2016
Citation Information: JCI Insight. 2016;1(4):e86183. https://doi.org/10.1172/jci.insight.86183.
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Clinical Research and Public Health Pulmonology

Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation 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 the G551D-CFTR mutation; 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.

FUNDING. This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.

Authors

Ryan J. Adam, Katherine B. Hisert, Jonathan D. Dodd, Brenda Grogan, Janice L. Launspach, Janel K. Barnes, Charles G. Gallagher, Jered P. Sieren, Thomas J. Gross, Anthony J. Fischer, Joseph E. Cavanaugh, Eric A. Hoffman, Pradeep K. Singh, Michael J. Welsh, Edward F. McKone, David A. Stoltz

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Figure 3

Ivacaftor rapidly improves air trapping.

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Ivacaftor rapidly improves air trapping. Studies were performed on day 0...
Studies were performed on day 0 (before ivacaftor) and following 2 days of ivacaftor treatment. (A) Total lung air trapping. Air trapping was defined as the percentage of voxels below –856 Hounsfield units (HU) on the RV (expiratory) CT scan. (B) Regional lung air trapping. (C) Correlation between air trapping (day 0) defined by the percentage of total lung voxels below –856 HU vs. air trapping defined by the RV/TLC ratio. The RV (expiratory) and TLC (inspiratory) lung volumes were determined from CT datasets (day 0). In individual panels, each symbol represents a different subject. In A and B, connected symbols represent individual subjects before and after ivacaftor. n = 12 subjects. Horizontal bars represent mean ±SEM. A Wilcoxon matched pairs signed-rank test (A) or a paired t test (B) was performed. A Pearson’s correlation coefficient (r) was determined for data in C. *P < 0.05. RV, residual volume; TLC, total lung capacity.