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J Cyst Fibros. 2020 Mar 20. pii: S1569-1993(20)30075-8. doi: 10.1016/j.jcf.2020.03.004. [Epub ahead of print]

Antibiofilm and mucolytic action of nitric oxide delivered via gas or macromolecular donor using in vitro and ex vivo models.

Author information

1
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
2
Marsico Lung Institute/CF Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Vast Therapeutics, Durham, NC, USA; UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: schoenfisch@unc.edu.

Abstract

BACKGROUND:

The combination of antibacterial and mucolytic actions makes nitric oxide (NO) an attractive dual-action cystic fibrosis (CF) therapeutic. The delivery of any therapeutic agent through pathological mucus is difficult, and the use of inhaled NO gas is inherently limited by toxicity concerns. Herein, we directly compare the ability of NO to eradicate infection and decrease mucus viscoelastic moduli as a function of delivery method (i.e., as a gas or water-soluble chitosan donor).

METHODS:

To compare bactericidal action in tissue, an ex vivo porcine lung model was infected and treated with either gaseous NO or NO-releasing chitosan for 5 h. In vitro Pseudomonas aeruginosa biofilm viability was quantified after NO treatment. Human bronchial epithelial mucus and CF sputum were exposed to NO and their viscoelastic moduli measured with parallel plate macrorheology.

RESULTS:

Larger NO concentrations were achieved in solution when delivered by chitosan relative to gas exposure. The bactericidal action in tissue of the NO-releasing chitosan was greater compared to NO gas in the infected tissue model. Chitosan delivery also resulted in improved antibiofilm action and reduced biofilm viability (2-log) while gaseous delivery had no impact at an equivalent dose (~0.8 µmol/mL). At equivalent NO doses, mucus and sputum rheology were significantly reduced after treatment with NO-releasing chitosan with NO gas having no significant effect.

CONCLUSIONS:

Delivery of NO by chitosan allows for larger in-solution concentrations than achievable via direct gas with superior bactericidal and mucolytic action.

KEYWORDS:

Biofilm; Cystic fibrosis; Mucolytic; Mucus; Nitric oxide; Pseudomonas aeruginosa

PMID:
32205069
DOI:
10.1016/j.jcf.2020.03.004

Conflict of interest statement

Declaration of Competing Interest The corresponding author declares competing financial interest. Mark Schoenfisch is a co-founder, member of the board of directors, and maintains a financial interest in Vast Therapeutics and KnowBIO, LLC. Vast Therapeutics is commercializing macromolecular nitric oxide storage and release scaffolds for the treatment of respiratory infections.

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