Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion

• Published in: American journal of physiology. Lung cellular and molecular physiology 2013-06, Vol.304 (11), p.L746-L756
• Main Authors: Tarran, Robert, Sabater, Juan R, Clarke, Tainya C, Tan, Chong D, Davies, Catrin M, Liu, Jia, Yeung, Arthur, Garland, Alaina L, Stutts, M Jackson, Abraham, William M, Phillips, Gary, Baker, William R, Wright, Clifford D, Wilbert, Sibylle
• Format: Article
• Language: English
• Subjects: Antibiotics; Azithromycin - pharmacology; Bacteria; Body fluids; Chronic obstructive pulmonary disease; Cystic fibrosis; Epithelial Sodium Channels - drug effects; Erythromycin - analogs & derivatives; Erythromycin - pharmacology; Humans; Leukocyte Elastase - antagonists & inhibitors; Leukocyte Elastase - metabolism; Lungs; Macrolides - pharmacology; Mucus - drug effects; Mucus - physiology; Respiratory Mucosa - drug effects; Respiratory System - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00292.2012

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2'-desoxy-9-(S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC₅₀ ~3.9 μM) and comparable to the antibacterial macrolide azithromycin (IC₅₀ ~2.4 μM). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance.