Elastic mucus strands impair mucociliary clearance in cystic fibrosis pigs

Abstract

Defective mucociliary transport contributes to infections and inflammation that destroy cystic fibrosis (CF) lungs. To better understand mechanisms that impair mucociliary transport, we tracked insufflated microdisks with X-ray computed tomography in spontaneously breathing CF pigs. Aerosolized saline increased microdisk movement toward the larynx. Surprisingly, forward progression was repeatedly interrupted as microdisks abruptly recoiled. Thus, although saline increased motion, it had minimal effects on microdisk clearance. To test if abnormally elastic mucus strands were responsible, we aerosolized Tris-carboxyethyl phosphine (TCEP), a reducing agent that breaks disulfide bonds linking mucins. TCEP largely eliminated retrograde movement and increased microdisk clearance. Ex vivo studies confirmed that TCEP broke CF mucus strands, unleashing them from submucosal gland ducts, and cilia carried them rostrally. These findings emphasize the role of abnormally elastic submucosal gland mucus strands in impairing CF mucociliary clearance and suggest that disrupting mucus strands may improve mucociliary clearance in CF.