Open AccessNovel Therapy of Bicarbonate, Glutathione, and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport
Author(s) -
Adegboyega Timothy Adewale,
Emily Falk Libby,
Lianwu Fu,
Andrew Lenzie,
Evan R. Boitet,
Susan E. Birket,
Courtney Fernandez Petty,
J. Dixon Johns,
Marina Mazur,
Guillermo J. Tearney,
Dan Copeland,
Carolyn Durham,
Steven M. Rowe
Publication year - 2020
Publication title -
american journal of respiratory cell and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.469
H-Index - 161
eISSN - 1535-4989
pISSN - 1044-1549
DOI - 10.1165/rcmb.2019-0287oc
Subject(s) - cystic fibrosis , cystic fibrosis transmembrane conductance regulator , mucociliary clearance , bicarbonate , ascorbic acid , mucus , chemistry , medicine , lung , biology , food science , ecology
Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o - cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o - F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.