Tromethamine improves mucociliary clearance in cystic fibrosis pigs
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 tr...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
|
| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15340 |
| _version_ | 1797397174829449216 |
|---|---|
| author | Jamison J. Ash Brieanna M. Hilkin Nicholas D. Gansemer Eric A. Hoffman Joseph Zabner David A. Stoltz Mahmoud H. Abou Alaiwa |
| author_facet | Jamison J. Ash Brieanna M. Hilkin Nicholas D. Gansemer Eric A. Hoffman Joseph Zabner David A. Stoltz Mahmoud H. Abou Alaiwa |
| author_sort | Jamison J. Ash |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T01:06:10Z |
| format | Article |
| id | doaj.art-e7ce31a60a064de3a40bb97a10f5ad50 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:06:10Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-e7ce31a60a064de3a40bb97a10f5ad502023-12-11T09:36:42ZengWileyPhysiological Reports2051-817X2022-09-011017n/an/a10.14814/phy2.15340Tromethamine improves mucociliary clearance in cystic fibrosis pigsJamison J. Ash0Brieanna M. Hilkin1Nicholas D. Gansemer2Eric A. Hoffman3Joseph Zabner4David A. Stoltz5Mahmoud H. Abou Alaiwa6Department of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Radiology Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USADepartment of Internal Medicine Pappajohn Biomedical Institute Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City Iowa USAAbstract 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.https://doi.org/10.14814/phy2.15340CT imagingcystic fibrosismucociliary transporttherapeutics |
| spellingShingle | Jamison J. Ash Brieanna M. Hilkin Nicholas D. Gansemer Eric A. Hoffman Joseph Zabner David A. Stoltz Mahmoud H. Abou Alaiwa Tromethamine improves mucociliary clearance in cystic fibrosis pigs Physiological Reports CT imaging cystic fibrosis mucociliary transport therapeutics |
| title | Tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| title_full | Tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| title_fullStr | Tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| title_full_unstemmed | Tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| title_short | Tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| title_sort | tromethamine improves mucociliary clearance in cystic fibrosis pigs |
| topic | CT imaging cystic fibrosis mucociliary transport therapeutics |
| url | https://doi.org/10.14814/phy2.15340 |
| work_keys_str_mv | AT jamisonjash tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT brieannamhilkin tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT nicholasdgansemer tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT ericahoffman tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT josephzabner tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT davidastoltz tromethamineimprovesmucociliaryclearanceincysticfibrosispigs AT mahmoudhaboualaiwa tromethamineimprovesmucociliaryclearanceincysticfibrosispigs |