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Updated: May 12, 2026
Label-free Neutrophil Enrichment from Patient-derived Airway Secretion Using Closed-loop Inertial Microfluidics
Published on: June 7, 2018
Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume
Robert Tarran1, Juan R Sabater, Tainya C Clarke
1Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, NC 27516, USA. robert_tarran@med.unc.edu
Abstract:
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.
Insights
A novel macrolide, GS-459755, prevents mucus dehydration in lung diseases like cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) by blocking epithelial sodium channel (ENaC) activation, without causing antibiotic resistance.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Cell Biology
Background:
- Mucus clearance is vital for lung defense, but mucus dehydration contributes to cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).
- Chronic macrolide antibiotics benefit CF and COPD patients but risk bacterial resistance.
- Human neutrophil elastase (HNE) exacerbates mucus stasis by activating the epithelial sodium channel (ENaC).
Purpose of the Study:
- To evaluate a novel macrolide, 2'-desoxy-9-(S)-erythromycylamine (GS-459755), for its potential to prevent HNE-induced mucus stasis.
- To assess GS-459755's impact on airway surface liquid (ASL) volume and ENaC activity in human bronchial epithelial cells (HBECs).
- To determine if GS-459755 offers therapeutic benefits for CF and COPD without antibiotic activity.
Main Methods:
- Tested GS-459755's effect on HNE activity and HNE-induced ASL volume depletion in HBECs.
- Assessed the dose-dependent effect of GS-459755 on ASL volume, comparing it to azithromycin.
- Measured the impact of macrolides on ciliary beat frequency (CBF), transepithelial water permeability, and amiloride-sensitive transepithelial voltage (a marker of ENaC activity).
Main Results:
- GS-459755 did not inhibit HNE activity but protected against HNE-induced ASL volume depletion in HBECs.
- The protective effect of GS-459755 on ASL volume was dose-dependent (IC₅₀ ~3.9 μM), similar to azithromycin (IC₅₀ ~2.4 μM).
- Macrolide pretreatment diminished amiloride-sensitive transepithelial voltage, indicating reduced ENaC activity, without affecting CBF or water permeability.
Conclusions:
- GS-459755 may mitigate HNE-induced ENaC activation, offering a potential treatment for mucus dehydration in CF and COPD.
- This novel macrolide provides therapeutic benefits for mucus clearance disorders without contributing to antibiotic resistance.
- GS-459755 represents a promising therapeutic strategy for managing CF and COPD by targeting mucus dehydration mechanisms.
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