title: Repurposing tromethamine as inhaled therapy to treat CF airway disease.
abstract: In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3-and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3-increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3--independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease.
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Mahmoud H
authors.initials: MH
authors.lastname: Abou Alaiwa
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Launspach
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Sheets
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Jade A
authors.initials: JA
authors.lastname: Rivera
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Gansemer
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Taft
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Thorne
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.|Department of Molecular Physiology and Biophysics.|Howard Hughes Medical Institute.|Pappajohn Biomedical Institute, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.|Department of Molecular Physiology and Biophysics.|Pappajohn Biomedical Institute, and.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stoltz
authors.affiliation: Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine.|Pappajohn Biomedical Institute, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner