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

Robert Tarran, Juan R. Sabater, Tainya C. Clarke, Chong D. Tan, Catrin M. Davies, Jia Liu, Arthur Yeung, Alaina L. Garland, M. Jackson Stutts, William M. Abraham, Gary Phillips, William R. Baker, Clifford D. Wright, Sibylle Wilbert

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume304
Issue number11
DOIs
StatePublished - Jun 11 2013
Externally publishedYes

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Leukocyte Elastase
Macrolides
Mucus
Cystic Fibrosis
Chronic Obstructive Pulmonary Disease
Dehydration
Inhibitory Concentration 50
Staphylococcal Pneumonia
Anti-Bacterial Agents
Epithelial Sodium Channels
Moraxella (Branhamella) catarrhalis
Azithromycin
Amiloride
Haemophilus influenzae
Streptococcus pneumoniae
2'-desoxy-9-erythromycylamine
Lung Diseases
Permeability
Chronic Disease
Epithelial Cells

Keywords

  • COPD
  • ENaC
  • Epithelia
  • Protease
  • Sodium absorption

ASJC Scopus subject areas

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

Cite this

Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion. / Tarran, Robert; Sabater, Juan R.; Clarke, Tainya C.; Tan, Chong D.; Davies, Catrin M.; Liu, Jia; Yeung, Arthur; Garland, Alaina L.; Jackson Stutts, M.; Abraham, William M.; Phillips, Gary; Baker, William R.; Wright, Clifford D.; Wilbert, Sibylle.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 304, No. 11, 11.06.2013.

Research output: Contribution to journalArticle

Tarran, R, Sabater, JR, Clarke, TC, Tan, CD, Davies, CM, Liu, J, Yeung, A, Garland, AL, Jackson Stutts, M, Abraham, WM, Phillips, G, Baker, WR, Wright, CD & Wilbert, S 2013, 'Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 304, no. 11. https://doi.org/10.1152/ajplung.00292.2012
Tarran, Robert ; Sabater, Juan R. ; Clarke, Tainya C. ; Tan, Chong D. ; Davies, Catrin M. ; Liu, Jia ; Yeung, Arthur ; Garland, Alaina L. ; Jackson Stutts, M. ; Abraham, William M. ; Phillips, Gary ; Baker, William R. ; Wright, Clifford D. ; Wilbert, Sibylle. / Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013 ; Vol. 304, No. 11.
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