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Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs

Li, Xiaopeng PhD1; Vargas Buonfiglio, Luis G. MD1; Adam, Ryan J. PhD1,2; Stoltz, David A. MD, PhD1,2,3; Zabner, Joseph MD1; Comellas, Alejandro P. MD1

doi: 10.1097/CCM.0000000000002720
Online Laboratory Investigations
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Objectives: To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema.

Design: Prospective laboratory animal investigation.

Setting: Animal research laboratory.

Subjects: Newborn and 3 days to 1 week old pigs.

Interventions: Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload.

Measurements and Main Results: Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor.

Conclusions: Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

Supplemental Digital Content is available in the text.

1Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.

2Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, IA.

3Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.

Supported, in part, by the National Institutes of Health (HL091842 and HL51670 to J.Z. and D.A.S., T32 HL007638 to R.J.A.) and by American Heart Association (14SDG18730009 to X.L.).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Drs. Li, Adam, Stoltz, Zabner, and Comellas received support for article research from the National Institutes of Health (NIH). Dr. Stoltz’s institution received funding from the NIH. Dr. Vargas Buonfiglio has disclosed that he does not have any potential conflicts of interest.

For information regarding this article, E-mail: Xiaopeng-Li@uiowa.edu

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