Journal article
Amphotericin B induces epithelial voltage responses in people with cystic fibrosis
Journal of cystic fibrosis, Vol.20(3), pp.540-550
05/01/2021
DOI: 10.1016/j.jcf.2020.11.018
PMCID: PMC8184863
PMID: 33309058
Abstract
Background: Approximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO3 & minus; secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people.
Methods: To determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators.
Results: AmB increased transepithelial Cl- current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation.
Conclusions: Our results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.
Details
- Title: Subtitle
- Amphotericin B induces epithelial voltage responses in people with cystic fibrosis
- Creators
- Rajeev S. Chorghade - University of Illinois Urbana-ChampaignBo Ram Kim - Roy J. and Lucille A. Carver College of MedicineJanice L. Launspach - Roy J. and Lucille A. Carver College of MedicinePhilip H. Karp - Roy J. and Lucille A. Carver College of MedicineMichael J. Welsh - Roy J. and Lucille A. Carver College of MedicineMartin D. Burke - University of Illinois Urbana-Champaign
- Resource Type
- Journal article
- Publication Details
- Journal of cystic fibrosis, Vol.20(3), pp.540-550
- DOI
- 10.1016/j.jcf.2020.11.018
- PMID
- 33309058
- PMCID
- PMC8184863
- NLM abbreviation
- J Cyst Fibros
- ISSN
- 1569-1993
- eISSN
- 1873-5010
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- 5R35GM118185; andHL091842 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 05/01/2021
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9984259441202771
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