Cyclic compression increases F508 Del CFTR expression in ciliated human airway epithelium

Author:

Marozkina Nadzeya1ORCID,Bosch Jürgen1,Cotton Calvin1,Smith Laura1,Seckler James1,Zaman Khalequz1ORCID,Rehman Shagufta2,Periasamy Ammasi2,Gaston Herbert3,Altawallbeh Ghaith1,Davis Michael4,Jones David R.5,Schilz Robert6,Randell Scott H.7,Gaston Benjamin18

Affiliation:

1. Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio

2. W. M. Keck Center for Cellular Imaging, Department of Biology, University of Virginia, Charlottesville, Virginia

3. Lake Effect Pharma, LLC, Gates Mills, Ohio

4. Department of Pediatrics, Division of Pulmonary Medicine, Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia

5. Thoracic Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York

6. Pulmonology and Critical Care Medicine University Hospitals, Cleveland, Ohio

7. Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina

8. Pediatric Pulmonology Division, Rainbow Babies and Children’s Hospital, Cleveland, Ohio

Abstract

The mechanisms by which transepithelial pressure changes observed during exercise and airway clearance can benefit lung health are challenging to study. Here, we have studied 117 mature, fully ciliated airway epithelial cell filters grown at air-liquid interface grown from 10 cystic fibrosis (CF) and 19 control subjects. These were exposed to cyclic increases in apical air pressure of 15 cmH2O for varying times. We measured the effect on proteins relevant to lung health, with a focus on the CF transmembrane regulator (CFTR). Immunoflourescence and immunoblot data were concordant in demonstrating that air pressure increased F508Del CFTR expression and maturation. This effect was in part dependent on the presence of cilia, on Ca2+ influx, and on formation of nitrogen oxides. These data provide a mechanosensory mechanism by which changes in luminal air pressure, like those observed during exercise and airway clearance, can affect epithelial protein expression and benefit patients with diseases of the airways.

Funder

NIH

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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