# Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis > **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $1,053,550 ## Abstract PROJECT SUMMARY Despite the development of new therapies, cystic fibrosis (CF) remains a life-shortening disease. Airway infec- tion and inflammation begin during infancy and lead to respiratory failure. Thus, early interventions aimed at correcting the initial host defense defects and preventing/reducing infection could dramatically improve the course of CF lung disease. It is well known that mutations in the gene encoding CFTR, a HCO – and Cl– con- 3 ducting channel, cause CF. Yet, the origins of CF lung disease have remained less well understood. We dis- covered that loss of CFTR impairs two important airway host defense mechanisms. a) Reduced activity of air- way surface liquid (ASL) antimicrobials. b) More viscous mucus that also has abnormal properties, impairing its ability to detach from submucosal gland ducts, thus hindering mucociliary transport (MCT). In both cases, loss of CFTR-mediated HCO3– secretion and an abnormally acidic pH are key factors. Our long-term goal is to develop novel therapeutics that target primary host defense defects due to loss of CFTR function. The overall objective of this proposal is to determine if airway alkalinization, with a repurposed drug, can prevent or allevi- ate the development of CF airway disease. Our hypothesis is that airway alkalinization with tromethamine (THAM, an FDA-approved alkalinizing agent in human clinical use for metabolic acidosis), will restore airway host defenses in CF and prevent/alleviate the development of CF airway disease. We found in humans and pigs that aerosolized THAM, a tris-based, non-bicarbonate buffer, causes a sustained increase in ASL pH and the effect lasts for hours, in contrast to a much shorter duration with NaHCO3. THAM enhanced ASL bacterial killing and decreased mucus viscosity. We test the following Specific Aims: Aim 1. Does aerosolized THAM produce a prolonged increase in ASL pH and enhance antimicrobial activity in pigs and humans? Based upon our published and unpublished data, our working hypothesis is that aerosolized THAM will increase ASL pH and restore ASL antimicrobial properties, in humans and pigs with CF. Aim 2. Will airway alkalinization im- prove MCT? From our earlier studies, we postulate that airway alkalinization with THAM will reverse MCT de- fects in CF, thereby enhancing MCT in CF. Aim 3. Does airway alkalinization alleviate or prevent early airway disease in CF pigs? Our published and preliminary data show that CF pigs already have airway host defense defects present at birth and develop airway disease within 3 weeks of age. Thus, we hypothesize that, in CF pigs, long-term restoration of ASL pH with THAM will improve airway host defense and lessen or prevent early airway disease in CF pigs. We are uniquely positioned to translate our recent discoveries on the pathogenesis of CF lung disease into a therapeutic intervention. These results, from both human and preclinical animal stud- ies, will be transformative for CF and likely other airw... ## Key facts - **NIH application ID:** 10155587 - **Project number:** 5R01HL136813-05 - **Recipient organization:** UNIVERSITY OF IOWA - **Principal Investigator:** DAVID A STOLTZ - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $1,053,550 - **Award type:** 5 - **Project period:** 2017-04-10 → 2023-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10155587 ## Citation > US National Institutes of Health, RePORTER application 10155587, Airway Alkalinization and Repurposing Tromethamine as a Therapeutic Approach in Cystic Fibrosis (5R01HL136813-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155587. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*