Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense

Author:

Li Xiaopeng1,Tang Xiao Xiao12,Vargas Buonfiglio Luis G.1,Comellas Alejandro P.1,Thornell Ian M.12,Ramachandran Shyam3,Karp Philip H.12,Taft Peter J.1,Sheets Kelsey1,Abou Alaiwa Mahmoud H.1,Welsh Michael J.124,Meyerholz David K.5ORCID,Stoltz David A.164,Zabner Joseph1

Affiliation:

1. Department of Internal Medicine, University of Iowa, Iowa City, Iowa;

2. Howard Hughes Medical Institute, Iowa City, Iowa;

3. Department of Pediatrics, University of Iowa, Iowa City, Iowa; and

4. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa;

5. Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa

6. Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa;

Abstract

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl and bicarbonate (HCO3) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl and HCO3 transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization.

Funder

Cystic Fibrosis Foundation (CFF)

HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)

Publisher

American Physiological Society

Subject

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

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