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.

TNFα and IL-17 alkalinize airway surface liquid through CFTR and pendrin

“…Inflammation is critical for host defense. Previous studies indicate that in the respiratory system, an acidic pH impairs, and an alkaline pH enhances two host defenses against bacteria, mucociliary transport and antimicrobial activity ( 1 , 2 , 9 , 19 , 66 , 77 , 80 , 88 ). Finding that TNFα and IL-17, important cytokine regulators of neutrophilic inflammation, increase pH ASL emphasizes the importance of an increased pH ASL in defending the respiratory tract.…”

Different expression about induced sputum cell sorting in the two main types of chronic obstructive pulmonary disease

“…An inhaled β2‐agonist (salbutamol, 200 mg) is then delivered to inhibit any possible bronchoconstriction from the saline inhalation, which is itself a bronchoconstrictive stimulus, and the FEV1 is remeasured. Hypertonic saline aerosol is then inhaled from a Medix ultrasonic nebulizer (previously known as Fisoneb), which has a relatively low output (0.87 mL/min) and a large particle size (5.58 mm aerodynamic mass median diameter) in concentrations of 3% followed by 4% and then 5%, each for an interval of 7 min. At the end of each inhalation, or earlier if symptoms of chest tightness or dyspnea develop, the FEV1 is measured again.…”

Catching Common Cold Virus with a Net: Pyridostatin Forms Filaments in Tris Buffer That Trap Viruses—A Novel Antiviral Strategy?

“…However, more work is required to find out whether the observed viral trapping could indeed be used in antiviral therapy. It had been shown that Tris, called ‘Tromethamine’ in the below citation, administered through nebulization alleviated respiratory problems resulting from cystic fibrosis [ 15 ]; adding the minimally toxic PDS to such solutions might be a way of application.…”