Defective Fluid Secretion from Submucosal Glands of Nasal Turbinates from CFTR-/- and CFTRΔF508/ΔF508 Pigs

Hyung-Ju Cho,Nam Soo Joo,Jeffrey J Wine,Neeraj Vij

doi:10.1371/journal.pone.0024424

Abstract

BackgroundCystic fibrosis (CF), caused by reduced CFTR function, includes severe sinonasal disease which may predispose to lung disease. Newly developed CF pigs provide models to study the onset of CF pathophysiology. We asked if glands from pig nasal turbinates have secretory responses similar to those of tracheal glands and if CF nasal glands show reduced fluid secretion.Methodology/Principal FindingsUnexpectedly, we found that nasal glands differed from tracheal glands in five ways, being smaller, more numerous (density per airway surface area), more sensitive to carbachol, more sensitive to forskolin, and nonresponsive to Substance P (a potent agonist for pig tracheal glands). Nasal gland fluid secretion from newborn piglets (12 CF and 12 controls) in response to agonists was measured using digital imaging of mucus bubbles formed under oil. Secretion rates were significantly reduced in all conditions tested. Fluid secretory rates (Controls vs. CF, in pl/min/gland) were as follows: 3 µM forskolin: 9.2±2.2 vs. 0.6±0.3; 1 µM carbachol: 143.5±35.5 vs. 52.2±10.3; 3 µM forskolin + 0.1 µM carbachol: 25.8±5.8 vs. CF 4.5±0.9. We also compared CFΔF508/ΔF508 with CFTR-/- piglets and found significantly greater forskolin-stimulated secretion rates in the ΔF508 vs. the null piglets (1.4±0.8, n = 4 vs. 0.2±0.1, n = 7). An unexpected age effect was also discovered: the ratio of secretion to 3 µM forskolin vs. 1 µM carbachol was ∼4 times greater in adult than in neonatal nasal glands.Conclusions/SignificanceThese findings reveal differences between nasal and tracheal glands, show defective fluid secretion in nasal glands of CF pigs, reveal some spared function in the ΔF508 vs. null piglets, and show unexpected age-dependent differences. Reduced nasal gland fluid secretion may predispose to sinonasal and lung infections.

Highlights

Cystic fibrosis (CF) occurs when CFTR anion channels, which are especially important in the functioning of ion transporting epithelia, are missing or defective
Conclusions/Significance: These findings reveal differences between nasal and tracheal glands, show defective fluid secretion in nasal glands of CF pigs, reveal some spared function in the DF508 vs. null piglets, and show unexpected agedependent differences
CF vs. control glands Nasal turbinate submucosal glands of one-day old CF piglets display a profound decrease in stimulated fluid secretion

Summary

Introduction

Cystic fibrosis (CF) occurs when CFTR anion channels, which are especially important in the functioning of ion transporting epithelia, are missing or defective. An elevated transepithelial difference across the nasal epithelium was the first electrophysiological signature of an ion transport defect in CF [1]. One goal of that research is to understand how altered epithelial ion and fluid transport predisposes the respiratory system to chronic bacterial infections, which are presently the most significant clinical feature of CF. In the non-CF population, CFTR mutations on one chromosome predispose to CRS [3], sometimes including bacterial biofilms on the nasal mucosa [4]. Cystic fibrosis (CF), caused by reduced CFTR function, includes severe sinonasal disease which may predispose to lung disease. We asked if glands from pig nasal turbinates have secretory responses similar to those of tracheal glands and if CF nasal glands show reduced fluid secretion

Methods

Results

Conclusion