Tromethamine improves mucociliary clearance in cystic fibrosis pigs

Jamison J. Ash; Brieanna M. Hilkin; Nicholas D. Gansemer; Eric A. Hoffman; Joseph Zabner; David A. Stoltz; Mahmoud H. Abou Alaiwa

doi:10.14814/phy2.15340

Back

Tromethamine improves mucociliary clearance in cystic fibrosis pigs

Journal article

Open access

Peer reviewed

Tromethamine improves mucociliary clearance in cystic fibrosis pigs

Jamison J. Ash, Brieanna M. Hilkin, Nicholas D. Gansemer, Eric A. Hoffman, Joseph Zabner, David A. Stoltz and Mahmoud H. Abou Alaiwa

Physiological reports, Vol.10(17), pp.e15340-n/a

09/2022

DOI: 10.14814/phy2.15340

PMCID: PMC9453173

PMID: 36073059

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453173View

Published (Version of record) Open Access

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. 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.

CT imaging

cystic fibrosis

mucociliary transport

therapeutics

Details

Title: Subtitle: Tromethamine improves mucociliary clearance in cystic fibrosis pigs
Creators: Jamison J. Ash - University of Iowa
Brieanna M. Hilkin - University of Iowa
Nicholas D. Gansemer - University of Iowa
Eric A. Hoffman - University of Iowa
Joseph Zabner - Roy J. and Lucille A. Carver College of Medicine
David A. Stoltz - Roy J. and Lucille A. Carver College of Medicine
Mahmoud H. Abou Alaiwa - University of Iowa
Resource Type: Journal article
Publication Details: Physiological reports, Vol.10(17), pp.e15340-n/a
DOI: 10.14814/phy2.15340
PMID: 36073059
PMCID: PMC9453173
NLM abbreviation: Physiol Rep
eISSN: 2051-817X
Number of pages: 11
Grant note: National Heart, Lung, and Blood Institute (NIH K08 HL135433; NIH PPG HL051670; NIH PPG HL091842; NIH R01 HL136813) Cystic Fibrosis Foundation (ABOU20A0‐KB; STOLTZ16XX0; STOLTZ19R0)
Language: English
Date published: 09/2022
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984297610602771

Metrics

16 Record Views

3 Times Cited - Web of Science