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Immunomodulatory Effects of a Low-Dose Clarithromycin-Based Macrolide Solution Pressurised Metered Dose Inhaler

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ABSTRACT

Purpose

The aim of this study was to assess the effects of low-dose clarithromycin, formulated as solution pressurized metered dose inhaler, following deposition on the Calu-3 respiratory epithelial cells.

Methods

Clarithromycin was deposited on the air-interface culture of Calu-3 cells using a modified Andersen cascade impactor. Transport of fluorescein-Na, production of mucus and interleukin-8 release from Calu-3 cells following stimulation with transforming growth factor-β and treatment with clarithromycin was investigated.

Results

The deposition of clarithromycin had significant effect on the permeability of fluorescein-Na, suggesting that the barrier integrity was improved following a short-term treatment with clarithromycin (apparent permeability values were reduced to 3.57 × 10-9 ± 2.32 × 10-9 cm.s-1, compared to 1.14 × 10-8 ± 4.30 × 10-8 cm.s-1 for control). Furthermore, the amount of mucus produced was significantly reduced during the course of clarithromycin treatment. The concentration of interleukin-8 secreted from Calu-3 cells following stimulation with transforming growth factor-β resulted in significantly lower level of interleukin-8 released from the cells pre-treated with clarithromycin (5.2 ± 0.5 ng.ml-1 clarithromycin treated vs. 7.7 ± 0.8 ng.ml-1 control, respectively).

Conclusions

Our data demonstrate that treatment with clarithromycin decreases the paracellular permeability of epithelial cells, mucus secretion and interleukin-8 release and therefore, inhaled clarithromycin holds potential as an anti-inflammatory therapy.

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Abbreviations

ABS:

Acrylonitrile butadiene styrene

ACI:

Andersen cascade impactor

AIC:

Air interface culture

CF:

Cystic fibrosis

COPD:

Chronic obstructive pulmonary disease

ELISA:

Enzyme-linked immunosorbent assay

FEV1 :

Forced expiratory volume in 1 second

flu-Na:

Fluorescein sodium

FVC:

Forced vital capacity

HBSS:

Hank’s Balanced Salt Solution

HFA:

Hydrofluoroalkane

IC50 :

Half maximal inhibitory concentration

IL:

Interleukin

JAMA:

Junction adhesion molecule-A

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

PBS:

Phosphate buffer solution

pMDIs:

Pressurised metered dose inhalers

RGB:

Red-green-blue

RSV:

Respiratory syncytial virus

TEER:

Transepithelial electrical resistance

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported under Australian Research Council's Discovery Projects funding scheme (project number DP120100251). A/Professor Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). A/Professor Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063).

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Author notes

  1. Mehra Haghi

    Present address: School of Pharmacy, Graduate School of Health, The University of Technology, PO Box 123, Broadway NSW 2007, Sydney, Australia

Authors and Affiliations

  1. Respiratory Technology Woolcock Institute of Medical Research and Discipline of Pharmacology, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia

    Mehra Haghi, Bing Zhu, Paul M. Young & Daniela Traini

  2. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

    Alessandro Saadat & Gaia Colombo

  3. Sydney Central Medical School, The University of Sydney, Sydney, NSW, Australia

    Gregory King

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  1. Mehra Haghi
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  2. Alessandro Saadat
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Correspondence to Daniela Traini.

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Haghi, M., Saadat, A., Zhu, B. et al. Immunomodulatory Effects of a Low-Dose Clarithromycin-Based Macrolide Solution Pressurised Metered Dose Inhaler. Pharm Res 32, 2144–2153 (2015). https://doi.org/10.1007/s11095-014-1605-y

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  • DOI: https://doi.org/10.1007/s11095-014-1605-y

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