Tromethamine improves mucociliary clearance in cystic fibrosis pigs. Issue 17 (8th September 2022)

• Record Type: Journal Article
• Authors: Ash, Jamison J.; Hilkin, Brieanna M.; Gansemer, Nicholas D.; Hoffman, Eric A.; Zabner, Joseph; Stoltz, David A.; Abou Alaiwa, Mahmoud H.
• Is Part Of: Physiological reports. Volume 10:Issue 17(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-08
• Subjects: CT imaging -- cystic fibrosis -- mucociliary transport -- therapeutics; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.15340
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: In cystic fibrosis (CF), the loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated Cl − and HCO3 − secretion across the epithelium acidifies the airway surface liquid (ASL). Acidic ASL alters two key host defense mechanisms: Rapid ASL bacterial killing and mucociliary transport (MCT). Aerosolized tromethamine (Tham) increases ASL pH and restores the ability of ASL to rapidly kill bacteria in CF pigs. In CF pigs, clearance of insufflated microdisks is interrupted due to abnormal mucus causing microdisks to abruptly recoil. Aerosolizing a reducing agent to break disulfide bonds that link mucins improves MCT. Here, we are interested in restoring MCT in CF by aerosolizing Tham, a buffer with a pH of 8.4. Because Tham is hypertonic to serum, we use an acidified formulation as a control. We measure MCT by tracking the caudal movement of individual tantalum microdisks with serial chest computed tomography scans. Alkaline Tham improves microdisk clearance to within the range of that seen in non‐CF pigs. It also partially reverses MCT defects, including reduced microdisk recoil and elapse time until they start moving after methacholine stimulation in CF pig airways. The effect is not due to hypertonicity, as it is not seen with acidified Tham or hypertonic saline. This finding indicates acidic ASL impairs CF MCT and suggests that alkalinization of ASL pH with inhaled Tham may improve CF airway disease. Abstract : Cystic fibrosis airways are acidic and as a result, submucosal gland secretions are abnormally elastic. Tromethamine, a tris buffer with long‐lasting effect on pH, alkalinizes the airways and reverses mucociliary clearance defects in CF.